{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:01:36Z","timestamp":1790834496730,"version":"4.1.0"},"reference-count":119,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      T cell mediated immunity (T-CMI) is an important component of effective host immunity against intracellular pathogens such as\n                      <jats:italic>Salmonella enterica<\/jats:italic>\n                      serovar Typhi (\n                      <jats:italic>S.<\/jats:italic>\n                      Typhi; ST). Baseline T-CMI responsiveness to\n                      <jats:italic>S.<\/jats:italic>\n                      Typhi has been previously described in healthy individuals, likely reflecting cross-reactive responsiveness to other\n                      <jats:italic>Enterobacteriaceae<\/jats:italic>\n                      within the gut microbiota. Interestingly, T cell baseline responsiveness has been associated with protection or susceptibility in a human challenge model following exposure to wild-type (wt) ST. To better understand the contribution of this baseline responsiveness to immunity against ST infection, an in-depth characterization of T cell immunity is needed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here, peripheral blood mononuclear cells from eighteen healthy volunteers with no history of typhoid fever vaccination or infection were co-cultured with autologous B-lymphoblastoid cell lines (B-LCL) previously infected with wt ST as antigen presenting cells. Non-infected B-LCL (NI) were used as controls. After 18\u00a0h or 40\u00a0h of stimulation, cells were stained with a 52-parameter mass cytometry antibody panel and analyzed using manual gating, dimensionality reduction and unsupervised clustering approaches. We studied conventional CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T memory cells, including T effector memory (T\n                      <jats:sub>EM<\/jats:sub>\n                      ), T\n                      <jats:sub>EM<\/jats:sub>\n                      re-expressing CD45RA (T\n                      <jats:sub>EMRA<\/jats:sub>\n                      ), and T central memory (T\n                      <jats:sub>CM<\/jats:sub>\n                      ), CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T stem cell memory (T\n                      <jats:sub>SCM<\/jats:sub>\n                      ), CD4\n                      <jats:sup>+<\/jats:sup>\n                      circulating T follicular helper (cT\n                      <jats:sub>FH<\/jats:sub>\n                      ), CD4\n                      <jats:sup>+<\/jats:sup>\n                      T regulatory (T\n                      <jats:sub>reg<\/jats:sub>\n                      ), and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T regulatory precursors (T\n                      <jats:sub>rp<\/jats:sub>\n                      ), as well as non-conventional CD8\n                      <jats:sup>+<\/jats:sup>\n                      mucosal associated invariant T (MAIT), T gamma delta (T\u03b3\u03b4), and Natural-Killer T (NKT) cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>All studied cell subsets showed significant (p&amp;lt;0.01) baseline responsiveness to ST-infected target cells when compared to NI target cells. Most functional responses were observed in activation, homing, and cytotoxicity markers across all conventional and non-conventional T cell subsets, defining in great depth the characteristics of baseline T-CMI to S. Typhi.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      This high-dimensional approach showed a complex interaction between distinct cell subsets with multifunctional properties and extended previous insights into the baseline T-CMI to\n                      <jats:italic>S.<\/jats:italic>\n                      Typhi. This will help guide future investigations of immunity in healthy individuals following infection or vaccination.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1940148","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:42:35Z","timestamp":1790833355000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Broad systemic T cell immunity to Salmonella enterica serovar Typhi in U.S. healthy adults"],"prefix":"10.3389","volume":"17","author":[{"given":"Laura E.","family":"Carreto-Binaghi","sequence":"first","affiliation":[{"name":"Center for Vaccine Development and Global Health, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]},{"name":"Department of Pediatrics, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayaum S.","family":"Booth","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and Global Health, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]},{"name":"Department of Pediatrics, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rezwanul","family":"Wahid","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and Global Health, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosangela","family":"Salerno-Goncalves","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and Global Health, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]},{"name":"Department of Pediatrics, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franklin R.","family":"Toapanta","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and Global Health, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo B.","family":"Sztein","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and Global Health, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]},{"name":"Department of Pediatrics, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]},{"name":"Department of Medicine, University of Maryland School of Medicine","place":["Baltimore, MD, United States"]},{"name":"Tumor Immunology and Immunotherapy Program, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center","place":["Baltimore, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41572-023-00480-z","article-title":"Typhoid fever","volume":"9","author":"Meiring","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00516","article-title":"Complex adaptive immunity to enteric fevers in humans: lessons learned and the path forward","volume":"5","author":"Sztein","year":"2014","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxz011","article-title":"Diversity of Salmonella Typhi-responsive CD4 and CD8 T cells before and after Ty21a typhoid vaccination in children and adults","volume":"31","author":"Rudolph","year":"2019","journal-title":"Int Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.clim.2019.04.002","article-title":"Characteristics of regulatory T-cell populations before and after Ty21a typhoid vaccination in children and adults","volume":"203","author":"Rudolph","year":"2019","journal-title":"Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1186\/s12967-020-02263-6","article-title":"Oral typhoid vaccine Ty21a elicits antigen-specific resident memory CD4(+) T cells in the human terminal ileum lamina propria and epithelial compartments","volume":"18","author":"Booth","year":"2020","journal-title":"J Transl Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2018.1564570","article-title":"Association between S. Typhi-specific memory CD4+ and CD8+ T responses in the terminal ileum mucosa and in peripheral blood elicited by the live oral typhoid vaccine Ty21a in humans","volume":"15","author":"Booth","year":"2019","journal-title":"Hum Vaccin Immunother"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00257","article-title":"Age-associated heterogeneity of Ty21a-induced T cell responses to HLA-E restricted Salmonella Typhi antigen presentation","volume":"10","author":"Rudolph","year":"2019","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/170.6.1508","article-title":"Cytokine production patterns and lymphoproliferative responses in volunteers orally immunized with attenuated vaccine strains of Salmonella typhi","volume":"170","author":"Sztein","year":"1994","journal-title":"J Infect Dis"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.4.2196","article-title":"Characterization of CD8(+) effector T cell responses in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine","volume":"169","author":"Salerno-Goncalves","year":"2002","journal-title":"J Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.728685","article-title":"B cells control mucosal-associated invariant T cell responses to Salmonella enterica serovar Typhi infection through the CD85j HLA-G receptor","volume":"12","author":"Salerno-Goncalves","year":"2021","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1128\/cvi.00234-10","article-title":"Ex vivo kinetics of early and long-term multifunctional human leukocyte antigen E-specific CD8+ cells in volunteers immunized with the Ty21a typhoid vaccine","volume":"17","author":"Salerno-Goncalves","year":"2010","journal-title":"Clin Vaccine Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038408","article-title":"Heterogeneity of multifunctional IL-17A producing S. Typhi-specific CD8+ T cells in volunteers following Ty21a typhoid immunization","volume":"7","author":"McArthur","year":"2012","journal-title":"PloS One"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.9.5852","article-title":"Identification of a human HLA-E-restricted CD8+ T cell subset in volunteers immunized with Salmonella enterica serovar Typhi strain Ty21a typhoid vaccine","volume":"173","author":"Salerno-Goncalves","year":"2004","journal-title":"J\u00a0Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.6.3521-3530.2005","article-title":"Immunization of volunteers with Salmonella enterica serovar Typhi strain Ty21a elicits the oligoclonal expansion of CD8+ T cells with predominant Vbeta repertoires","volume":"73","author":"Salerno-Goncalves","year":"2005","journal-title":"Infect Immun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2017.08.002","article-title":"Systemic and terminal ileum mucosal immunity elicited by oral immunization with the Ty21a typhoid vaccine in humans","volume":"4","author":"Booth","year":"2017","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxy070","article-title":"Effect of the live oral attenuated typhoid vaccine, Ty21a, on systemic and terminal ileum mucosal CD4+ T memory responses in humans","volume":"31","author":"Booth","year":"2019","journal-title":"Int Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.155.8.3987","article-title":"Cytotoxic T lymphocytes after oral immunization with attenuated vaccine strains of Salmonella typhi in humans","volume":"155","author":"Sztein","year":"1995","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a029546","article-title":"Is a human CD8 T-cell vaccine possible, and if so, what would it take? CD8 T-cell-mediated protective immunity and vaccination against enteric bacteria","volume":"10","author":"Sztein","year":"2018","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2022.104572","article-title":"Mucosal-associated invariant T cells exhibit distinct functional signatures associated with protection against typhoid fever","volume":"378","author":"Salerno-Goncalves","year":"2022","journal-title":"Cell Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.983403","article-title":"Controlled human infectious models, a path forward in uncovering immunological correlates of protection: Lessons from enteric fevers studies","volume":"13","author":"Sztein","year":"2022","journal-title":"Front Microbiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-016-0819-7","article-title":"Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans","volume":"14","author":"Fresnay","year":"2016","journal-title":"J Transl Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004914","article-title":"Activation of Salmonella Typhi-specific regulatory T cells in typhoid disease in a wild-type S. Typhi challenge model","volume":"11","author":"McArthur","year":"2015","journal-title":"PloS Pathog"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00398","article-title":"Challenge of humans with wild-type Salmonella enterica serovar Typhi elicits changes in the activation and homing characteristics of mucosal-associated invariant T cells","volume":"8","author":"Salerno-Goncalves","year":"2017","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003837","article-title":"Oral wild-type Salmonella Typhi challenge induces activation of circulating monocytes and dendritic cells in individuals who develop typhoid disease","volume":"9","author":"Toapanta","year":"2015","journal-title":"PloS NeglTrop Dis"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004766","article-title":"Oral challenge with wild-type Salmonella Typhi induces distinct changes in B cell subsets in individuals who develop typhoid disease","volume":"10","author":"Toapanta","year":"2016","journal-title":"PloS NeglTrop Dis"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00686-18","article-title":"Compositional and functional differences in the human gut microbiome correlate with clinical outcome following infection with wild-type Salmonella enterica serovar Typhi","volume":"9","author":"Zhang","year":"2018","journal-title":"mBio"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1384642","article-title":"Role of circulating T follicular helper subsets following Ty21a immunization and oral challenge with wild type S. Typhi in humans","volume":"15","author":"Booth","year":"2024","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1454857","article-title":"Changes in monocyte subsets in volunteers who received an oral wild-type Salmonella Typhi challenge and reached typhoid diagnosis criteria","volume":"15","author":"Toapanta","year":"2024","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00208","article-title":"Importance of Salmonella Typhi-responsive CD8+ T cell immunity in a human typhoid fever challenge model","volume":"8","author":"Fresnay","year":"2017","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ673","article-title":"Control of invasive Salmonella disease in Africa: Is there a role for human challenge models","volume":"61","author":"Gibani","year":"2015","journal-title":"Clin Infect Dis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02582","article-title":"IgA and IgG1 specific to Vi polysaccharide of Salmonella Typhi correlate with protection status in a typhoid fever controlled human infection model","volume":"10","author":"Dahora","year":"2019","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.coi.2017.07.009","article-title":"MAIT cells in infectious diseases","volume":"48","author":"Salou","year":"2017","journal-title":"Curr Opin Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s10156-013-0638-1","article-title":"The role of invariant natural killer T cells in microbial immunity","volume":"19","author":"Kinjo","year":"2013","journal-title":"J Infect Chemother"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1072","article-title":"Emerging role of gammadelta T cells in vaccine-mediated protection from infectious diseases","volume":"8","author":"Dantzler","year":"2019","journal-title":"Clin Transl Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100363","article-title":"Duration of antigen availability influences the expansion and memory differentiation of T cells","volume":"187","author":"Blair","year":"2011","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1178","article-title":"Human Salmonella Typhi exposure generates differential multifunctional cross\u2010reactive T\u2010cell memory responses against Salmonella Paratyphi and invasive nontyphoidal Salmonella","volume":"9","author":"Rapaka","year":"2020","journal-title":"Clin Trans Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038926","article-title":"The duration of antigen-stimulation significantly alters the diversity of multifunctional CD4 T cells measured by intracellular cytokine staining","volume":"7","author":"Kaveh","year":"2012","journal-title":"PloS One"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/cells6030029","article-title":"Delayed activation kinetics of Th2- and Th17 cells compared to Th1 cells","volume":"6","author":"Duechting","year":"2017","journal-title":"Cells"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.18502\/ijaai.v20i3.6338","article-title":"The effect of antigen dose and antigen presenting process on T cell stimulation: A method for enrichment of TB10.4 antigen-specific T-cell clones","volume":"20","author":"Motiee","year":"2021","journal-title":"Iran J Allergy Asthma Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3109\/14653240903136987","article-title":"Optimization and validation of a robust human T-cell culture method for monitoring phenotypic and polyfunctional antigen-specific CD4 and CD8 T-cell responses","volume":"11","author":"Lin","year":"2009","journal-title":"Cytotherapy"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000699","article-title":"T cell detection of a B-cell tropic virus infection: newly-synthesised versus mature viral proteins as antigen sources for CD4 and CD8 epitope display","volume":"5","author":"Mackay","year":"2009","journal-title":"PloS Pathog"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0200540","article-title":"MARCH1-mediated ubiquitination of MHC II impacts the MHC I antigen presentation pathway","volume":"13","author":"Wilson","year":"2018","journal-title":"PloS One"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00586","article-title":"Salmonella modulates B cell biology to evade CD8(+) T cell-mediated immune responses","volume":"5","author":"Lopez-Medina","year":"2014","journal-title":"Front Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.5.2734","article-title":"Concomitant induction of CD4+ and CD8+ T cell responses in volunteers immunized with Salmonella enterica serovar typhi strain CVD 908-htrA","volume":"170","author":"Salerno-Goncalves","year":"2003","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2024.103343","article-title":"Protocol for flow cytometry immunophenotyping of human antigen-specific T cells by activation-induced marker and Th1 cytokine detection","volume":"6","author":"Rotta","year":"2025","journal-title":"STAR Protoc"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100758","article-title":"A T-cell-based immunogenicity protocol for evaluating human antigen-specific responses","volume":"2","author":"Cimen Bozkus","year":"2021","journal-title":"STAR Protoc"},{"key":"B47","doi-asserted-by":"publisher","first-page":"13581","DOI":"10.1038\/s41598-020-70492-2","article-title":"Salmonella enterica serovar Typhi exposure elicits ex vivo cell-type-specific epigenetic changes in human gut cells","volume":"10","author":"Sztein","year":"2020","journal-title":"Sci Rep"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.24501","article-title":"PeacoQC: Peak-based selection of high quality cytometry data","volume":"101","author":"Emmaneel","year":"2022","journal-title":"Cytometry A"},{"key":"B49","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/1471-2105-7-123","article-title":"Detecting outliers when fitting data with nonlinear regression - a new method based on robust nonlinear regression and the false discovery rate","volume":"7","author":"Motulsky","year":"2006","journal-title":"BMC Bioinf"},{"key":"B50","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s13073-021-00918-7","article-title":"Maintenance of the human memory T cell repertoire by subset and tissue site","volume":"13","author":"Miron","year":"2021","journal-title":"Genome Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a037796","article-title":"Area under immunosurveillance: Dedicated roles of memory CD8 T-cell subsets","volume":"12","author":"Parga-Vidal","year":"2020","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201343751","article-title":"The who's who of T-cell differentiation: Human memory T-cell subsets","volume":"43","author":"Mahnke","year":"2013","journal-title":"Eur J Immunol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/nri3567","article-title":"Human memory T cells: Generation, compartmentalization and homeostasis","volume":"14","author":"Farber","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1084\/jem.186.9.1407","article-title":"Phenotypic and functional separation of memory and effector human CD8+ T cells","volume":"186","author":"Hamann","year":"1997","journal-title":"J Exp Med"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101400","article-title":"Follicular helper CD4 T cells (TFH)","volume":"29","author":"Crotty","year":"2011","journal-title":"Annu Rev Immunol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/nm.4241","article-title":"T memory stem cells in health and disease","volume":"23","author":"Gattinoni","year":"2017","journal-title":"Nat Med"},{"key":"B57","doi-asserted-by":"publisher","first-page":"120","DOI":"10.21037\/atm.2017.02.28","article-title":"Human stem memory T cells (T(SCM)) as critical players in the long-term persistence of immune responses","volume":"5","author":"Morrot","year":"2017","journal-title":"Ann Transl Med"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2005523","article-title":"Human TSCM cell dynamics in vivo are compatible with long-lived immunological memory and stemness","volume":"16","author":"Costa Del Amo","year":"2018","journal-title":"PloS Biol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1055805","article-title":"Identification and classification of distinct surface markers of T regulatory cells","volume":"13","author":"Wegrzyn","year":"2022","journal-title":"Front Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2025-4080","article-title":"CD8(+)HLA-DR(+)CD27(+) T cells define a population of naturally occurring regulatory precursors in humans","volume":"11","author":"Guo","year":"2025","journal-title":"Sci Adv"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1002\/cpim.90","article-title":"Characterization of human mucosal-associated invariant T (MAIT) cells","volume":"127","author":"Souter","year":"2019","journal-title":"Curr Protoc Immunol"},{"key":"B62","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/eji.201343509","article-title":"CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner","volume":"44","author":"Ussher","year":"2014","journal-title":"Eur J Immunol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1148988","article-title":"Deep characterization of human gammadelta T cell subsets defines shared and lineage-specific traits","volume":"14","author":"Sanz","year":"2023","journal-title":"Front Immunol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12248","article-title":"The peripheral differentiation of human natural killer T cells","volume":"97","author":"Liu","year":"2019","journal-title":"Immunol Cell Biol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.3855\/jidc.2019","article-title":"T-cell response to bacterial agents","volume":"5","author":"D'Elios","year":"2011","journal-title":"J Infect Dev Ctries"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21176144","article-title":"T cell immunity to bacterial pathogens: Mechanisms of immune control and bacterial evasion","volume":"21","author":"Shepherd","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B67","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/s41392-023-01471-y","article-title":"T cells in health and disease","volume":"8","author":"Sun","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01590-2","article-title":"Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology","volume":"24","author":"Mettelman","year":"2023","journal-title":"Nat Immunol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00809-x","article-title":"The impact of pre-existing cross-reactive immunity on SARS-CoV-2 infection and vaccine responses","volume":"23","author":"Murray","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh1823","article-title":"Cross-reactive CD4(+) T cells enhance SARS-CoV-2 immune responses upon infection and vaccination","volume":"374","author":"Loyal","year":"2021","journal-title":"Science"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07575-x","article-title":"Human SARS-CoV-2 challenge uncovers local and systemic response dynamics","volume":"631","author":"Lindeboom","year":"2024","journal-title":"Nature"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26083494","article-title":"Single-cell RNA sequencing of baseline immune profiles after third vaccination associated with subsequent SARS-CoV-2 infection in naive individuals","volume":"26","author":"Kang","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0389-z","article-title":"Pre-existing immunity to SARS-CoV-2: The knowns and unknowns","volume":"20","author":"Sette","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00174-20","article-title":"The changing face of the family Enterobacteriaceae (Order: \"Enterobacterales\"): New members, taxonomic issues, geographic expansion, and new diseases and disease syndromes","volume":"34","author":"Janda","year":"2021","journal-title":"Clin Microbiol Rev"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1186\/s43141-023-00622-6","article-title":"Mapping of conserved immunodominant epitope peptides in the outer membrane porin (Omp) L of prominent Enterobacteriaceae pathogens associated with gastrointestinal infections","volume":"21","author":"Kolla","year":"2023","journal-title":"J Genet Eng Biotechnol"},{"key":"B76","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s12917-025-04479-4","article-title":"Epitope mapping of recombinant Salmonella enterica serotype Heidelberg flagellar hook-associated protein by in silico and in vivo approaches","volume":"21","author":"Yeh","year":"2025","journal-title":"BMC Vet Res"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1097(94)90510-x","article-title":"Salmonella typhimurium enterotoxin epitopes shared among bacteria","volume":"118","author":"Chopra","year":"1994","journal-title":"FEMS Microbiol Lett"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines12111212","article-title":"Differential adjuvant activity by flagellins from Escherichia coli, Salmonella enterica serotype Typhimurium, and Pseudomonas aeruginosa","volume":"12","author":"Pang","year":"2024","journal-title":"Vaccines"},{"key":"B79","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/nbt.4314","article-title":"Dimensionality reduction for visualizing single-cell data using UMAP","volume":"37","author":"Becht","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.24320","article-title":"Current trends in flow cytometry automated data analysis software","volume":"99","author":"Cheung","year":"2021","journal-title":"Cytometry A"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1101\/047613","article-title":"Comparison of clustering methods for high-dimensional single-cell flow and mass cytometry data","volume":"89","author":"Weber","year":"2016","journal-title":"Cytometry A"},{"key":"B82","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1002\/eji.201545774","article-title":"The end of gating? An introduction to automated analysis of high dimensional cytometry data","volume":"46","author":"Mair","year":"2016","journal-title":"Eur J Immunol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1038\/ni1002","article-title":"Mechanism of CD1d-restricted natural killer T cell activation during microbial infection","volume":"4","author":"Brigl","year":"2003","journal-title":"Nat Immunol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425846","article-title":"The role of CD1d-restricted NK T lymphocytes in the immune response to oral infection with Salmonella typhimurium","volume":"35","author":"Berntman","year":"2005","journal-title":"Eur J Immunol"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/nature03408","article-title":"Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections","volume":"434","author":"Mattner","year":"2005","journal-title":"Nature"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.7.1121","article-title":"The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells","volume":"189","author":"Kitamura","year":"1999","journal-title":"J Exp Med"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2016.08.003","article-title":"NKT cell activation by Leishmania mexicana LPG: Description of a novel pathway","volume":"222","author":"Zamora-Chimal","year":"2017","journal-title":"Immunobiology"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2013.07.014","article-title":"Genetic boundaries to delineate the typhoid agent and other Salmonella serotypes into distinct natural lineages","volume":"102","author":"Tang","year":"2013","journal-title":"Genomics"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.08.054","article-title":"TCR- or cytokine-activated CD8(+) mucosal-associated invariant T cells are rapid polyfunctional effectors that can coordinate immune responses","volume":"28","author":"Lamichhane","year":"2019","journal-title":"Cell Rep"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2019.10.020","article-title":"Differential functional patterns of memory CD4(+) and CD8(+) T-cells from volunteers immunized with Ty21a typhoid vaccine observed using a recombinant Escherichia coli system expressing S. Typhi proteins","volume":"38","author":"Salerno-Goncalves","year":"2020","journal-title":"Vaccine"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abl6322","article-title":"Intrinsic IL-2 production by effector CD8 T cells affects IL-2 signaling and promotes fate decisions, stemness, and protection","volume":"7","author":"Kahan","year":"2022","journal-title":"Sci Immunol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.210.supp.164.04","article-title":"The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1(+) CD8(+) T cells in chronic viral infection","volume":"56","author":"Marx","year":"2023","journal-title":"Immunity"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2009.91","article-title":"Intracellular versus extracellular granzyme B in immunity and disease: Challenging the dogma","volume":"89","author":"Boivin","year":"2009","journal-title":"Lab Invest"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/nri911","article-title":"Functional significance of the perforin\/granzyme cell death pathway","volume":"2","author":"Trapani","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"B95","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.jim.2004.08.008","article-title":"CD107a as a functional marker for the identification of natural killer cell activity","volume":"294","author":"Alter","year":"2004","journal-title":"J Immunol Methods"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1038\/nri1570","article-title":"MHC class I molecules and KIRs in human history, health and survival","volume":"5","author":"Parham","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2024.10.006","article-title":"The peptide selectivity model: Interpreting NK cell KIR-HLA-I binding interactions and their associations to human diseases","volume":"45","author":"Sim","year":"2024","journal-title":"Trends Immunol"},{"key":"B98","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/0008-8749(88)90073-1","article-title":"Regulation of HLA-DR, DP, and DQ expression in activated T cells","volume":"117","author":"Gansbacher","year":"1988","journal-title":"Cell Immunol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0192883","article-title":"Dynamics of monocytic HLA-DR expression differs between bacterial etiologies during the course of bloodstream infection","volume":"13","author":"Cajander","year":"2018","journal-title":"PloS One"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0182427","article-title":"Human leucocyte antigen (HLA-DR) gene expression is reduced in sepsis and correlates with impaired TNFalpha response: A diagnostic tool for immunosuppression","volume":"12","author":"Winkler","year":"2017","journal-title":"PloS One"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2022-170987","article-title":"HLA-DR+ CD38high expression in T cells is excellent in quantifying the amplitude of T-cell activation in a spectrum of hyperinflammatory disorders including HLH","volume":"140","author":"Nguyen","year":"2022","journal-title":"Blood"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.07.008","article-title":"Frequency of HLA-DR(+)CD38(hi) T cells identifies and quantifies T-cell activation in hemophagocytic lymphohistiocytosis, hyperinflammation, and immune regulatory disorders","volume":"153","author":"Nguyen","year":"2024","journal-title":"J Allergy Clin Immunol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1653970","article-title":"HLA-DR expression in cytotoxic T lymphocytes: a key to boost the therapeutic potential of T cell-based strategies for breast cancer","volume":"16","author":"Salvador","year":"2025","journal-title":"Front Immunol"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13153841","article-title":"Expression of HLA-DR in cytotoxic T lymphocytes: a validated predictive biomarker and a potential therapeutic strategy in breast cancer","volume":"13","author":"Saraiva","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1038\/35037728","article-title":"CD95's deadly mission in the immune system","volume":"407","author":"Krammer","year":"2000","journal-title":"Nature"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.163.3.1315","article-title":"Primed T cells are more resistant to Fas-mediated activation-induced cell death than naive T cells","volume":"163","author":"Inaba","year":"1999","journal-title":"J Immunol"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1038\/35005523","article-title":"ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28","volume":"397","author":"Hutloff","year":"1999","journal-title":"Nature"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.06.001","article-title":"The costimulatory molecule ICOS limits memory-like properties and function of exhausted PD-1(+)CD8(+) T cells","volume":"58","author":"Humblin","year":"2025","journal-title":"Immunity"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2009.02.011","article-title":"IL-2- and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets","volume":"123","author":"Letourneau","year":"2009","journal-title":"J Allergy Clin Immunol"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1038\/nri1248","article-title":"CD28-mediated co-stimulation: a quantitative support for TCR signalling","volume":"3","author":"Acuto","year":"2003","journal-title":"Nat Rev Immunol"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2016.02.004","article-title":"CD28 costimulatory signals in T lymphocyte activation: Emerging functions beyond a qualitative and quantitative support to TCR signalling","volume":"28","author":"Porciello","year":"2016","journal-title":"Cytokine Growth Factor Rev"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00774.x","article-title":"Timing and tuning of CD27-CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology","volume":"229","author":"Nolte","year":"2009","journal-title":"Immunol Rev"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2013.61","article-title":"CD8(+) cells regulate the T helper-17 response in an experimental murine model of Sjogren syndrome","volume":"7","author":"Zhang","year":"2014","journal-title":"Mucosal Immunol"},{"key":"B114","doi-asserted-by":"publisher","first-page":"6580","DOI":"10.1038\/s41467-025-61647-8","article-title":"ST2\/IL-33 axis blockade inhibits regulatory T cell cytotoxicity towards CD8 T cells in the leukemic niche","volume":"16","author":"Jiang","year":"2025","journal-title":"Nat Commun"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1038\/nri2297","article-title":"CCR7 and its ligands: balancing immunity and tolerance","volume":"8","author":"Forster","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.090501.080131","article-title":"Ligands for L-selectin: homing, inflammation, and beyond","volume":"22","author":"Rosen","year":"2004","journal-title":"Annu Rev Immunol"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2010.158","article-title":"CXCR3 ligands: redundant, collaborative and antagonistic functions","volume":"89","author":"Groom","year":"2011","journal-title":"Immunol Cell Biol"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.5.761","article-title":"Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity","volume":"192","author":"Kunkel","year":"2000","journal-title":"J Exp Med"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90305-a","article-title":"Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1","volume":"74","author":"Berlin","year":"1993","journal-title":"Cell"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1940148\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:42:37Z","timestamp":1790833357000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1940148\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":119,"alternative-id":["10.3389\/fimmu.2026.1940148"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1940148","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"article-number":"1940148"}}