{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:41:08Z","timestamp":1764225668555,"version":"3.46.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100022370","name":"Global Challenges Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100022370","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>Regulatory T cells (Tregs) have been reported to control immune responses in microbial infections. However, their possible role in visceral leishmaniasis (VL) has not been well defined. To address this, we carried out extensive studies to investigate the frequency, phenotype and functions of kala-azar patients\u2019 peripheral blood Tregs pre and post treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Fresh blood and peripheral blood mononuclear cells (PBMCs) were used to delineate the frequency and phenotype in VL through flow cytometry. Further for functional characterization, PBMCs of VL patients were depleted of CD25\n                      <jats:sup>+<\/jats:sup>\n                      T cells and sorted Treg and T effector cells were co-cultured.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Tregs frequencies were significantly upregulated in the active VL patients compared to healthy controls and recovered individuals. Tregs characterized as CD4\n                      <jats:sup>+<\/jats:sup>\n                      CD127\n                      <jats:sup>-\/low<\/jats:sup>\n                      CD25\n                      <jats:sup>high<\/jats:sup>\n                      T cells expressed FoxP3 maximally. Isolated Treg cells from VL subjects displayed immunosuppression by inhibiting proliferation and IFN-\u03b3 production of effector cells. Moreover, Treg cells were functionally competent and exerted their suppressive role by inhibiting the IFN-\u03b3 production and proliferation of effector T cells. Interestingly, when analyzing Treg heterogeneity using the CD45RA marker, we observed an increased frequency of not only effector Treg subpopulations but also na\u00efve and non-Treg cells in active VL patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The present study characterizes the frequency, phenotype and function of CD4\n                      <jats:sup>+<\/jats:sup>\n                      CD127\n                      <jats:sup>-\/low<\/jats:sup>\n                      CD25\n                      <jats:sup>high<\/jats:sup>\n                      Treg cells of kala-azar patients\n                      <jats:italic>ex vivo<\/jats:italic>\n                      . Our results suggest that functional effector Treg subpopulation elevated during active VL modulate effectors of immune response and induce immunosuppression. These together with na\u00efve and non-Tregs cells constitute a defining feature of VL pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1676937","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:29:56Z","timestamp":1764224996000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional and phenotypic analysis of CD4 T cell dynamics in peripheral blood of human visceral leishmaniasis patients confers increased frequencies of CD25 expressing regulatory T cells that contribute to disease pathogenesis"],"prefix":"10.3389","volume":"16","author":[{"given":"Mohd","family":"Kamran","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Smriti","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pradyot","family":"Bhattacharya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sneha Ghosh","family":"Chaudhury","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anirban","family":"Bhattacharyya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Banik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad","family":"Asad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarfaraz Ahmad","family":"Ejazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Major","family":"Madhukar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krishna","family":"Pandey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehebubar","family":"Rahman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rama Prosad","family":"Goswami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nahid","family":"Ali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.138.3.908","article-title":"An analysis of T cell responsiveness in Indian kala-azar","volume":"138","author":"Sacks","year":"1987","journal-title":"J Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.8.5592","article-title":"IL-10- and TGF-beta-mediated susceptibility in kala-azar and post-kala-azar dermal leishmaniasis: the significance of amphotericin B in the control of Leishmania donovani infection in India","volume":"179","author":"Saha","year":"2007","journal-title":"J Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00143-12","article-title":"Reassessment of immune correlates in human visceral leishmaniasis as defined by cytokine release in whole blood","volume":"19","author":"Singh","year":"2012","journal-title":"Clin Vaccine Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"275253","DOI":"10.1155\/2013\/275253","article-title":"Post-kala-azar dermal leishmaniasis: A paradigm of paradoxical immune reconstitution syndrome in non-HIV\/AIDS patients","volume":"2013","author":"Khalil","year":"2013","journal-title":"J Trop Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00018","article-title":"Liposomal elongation factor-1alpha triggers effector CD4 and CD8 T cells for induction of long-lasting protective immunity against visceral leishmaniasis","volume":"9","author":"Sabur","year":"2018","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004422","article-title":"Induction of IL-10 and TGFbeta from CD4+CD25+FoxP3+ T cells correlates with parasite load in Indian kala-azar patients infected with leishmania donovani","volume":"10","author":"Bhattacharya","year":"2016","journal-title":"PloS Negl Trop Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.10.012","article-title":"Regulatory T-cells in autoimmune diseases: challenges, controversies and\u2013yet\u2013unanswered questions","volume":"14","author":"Grant","year":"2015","journal-title":"Autoimmun Rev"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.2.387","article-title":"Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation","volume":"184","author":"Asano","year":"1996","journal-title":"J Exp Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200737593","article-title":"Regulatory T cells - a brief history and perspective","author":"Sakaguchi","year":"2007","journal-title":"Eur J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.3.1245","article-title":"CD4+CD25high regulatory cells in human peripheral blood","volume":"167","author":"Baecher-Allan","year":"2001","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00178","article-title":"Multiple treg suppressive modules and their adaptability","volume":"3","author":"Wing","year":"2012","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12168","article-title":"Functional dynamics of Foxp3(+) regulatory T cells in mice and humans","volume":"259","author":"Bin Dhuban","year":"2014","journal-title":"Immunol Rev"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20060772","article-title":"CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells","volume":"203","author":"Liu","year":"2006","journal-title":"J Exp Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00616","article-title":"EB1\u20133 chain of IL-35 along with TGF-beta synergistically regulate anti-leishmanial immunity","volume":"10","author":"Asad","year":"2019","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701582","article-title":"Distinct Roles for CD4(+) Foxp3(+) Regulatory T Cells and IL-10-Mediated Immunoregulatory Mechanisms during Experimental Visceral Leishmaniasis Caused by Leishmania donovani","volume":"201","author":"Bunn","year":"2018","journal-title":"J Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1517\/14712598.3.6.875","article-title":"The role of CD4(+)CD25(+) regulatory T cells in Leishmania infection","volume":"3","author":"Belkaid","year":"2003","journal-title":"Expert Opin Biol Ther"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nri2189","article-title":"Regulatory T cells and infection: a dangerous necessity","volume":"7","author":"Belkaid","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nature01152","article-title":"CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity","volume":"420","author":"Belkaid","year":"2002","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2006.05.014","article-title":"Parasites and immunoregulatory T cells","volume":"18","author":"Belkaid","year":"2006","journal-title":"Curr Opin Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040298","article-title":"Role for CD4(+) CD25(+) regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity","volume":"200","author":"Mendez","year":"2004","journal-title":"J Exp Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.4.2517","article-title":"IL-10 from regulatory T cells determines vaccine efficacy in murine Leishmania major infection","volume":"175","author":"Stober","year":"2005","journal-title":"J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2008.07.001","article-title":"Identification of regulatory T cells during experimental Leishmania infantum infection","volume":"214","author":"Rodrigues","year":"2009","journal-title":"Immunobiology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01398-08","article-title":"Intralesional regulatory T-cell suppressive function during human acute and chronic cutaneous leishmaniasis due to Leishmania guyanensis","volume":"77","author":"Bourreau","year":"2009","journal-title":"Infect Immun"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1086\/596508","article-title":"In leishmaniasis due to Leishmania guyanensis infection, distinct intralesional interleukin-10 and Foxp3 mRNA expression are associated with unresponsiveness to treatment","volume":"199","author":"Bourreau","year":"2009","journal-title":"J Infect Dis"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1086\/502980","article-title":"CD4+CD25+ T cells in skin lesions of patients with cutaneous leishmaniasis exhibit phenotypic and functional characteristics of natural regulatory T cells","volume":"193","author":"Campanelli","year":"2006","journal-title":"J Infect Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2013.08.269","article-title":"Characterization of regulatory T cell (Treg) function in patients infected with Leishmania Braziliensis","volume":"74","author":"Costa","year":"2013","journal-title":"Hum Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3024.2010.01219.x","article-title":"Human visceral leishmaniasis is not associated with expansion or accumulation of Foxp3+ CD4 cells in blood or spleen","volume":"32","author":"Maurya","year":"2010","journal-title":"Parasite Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061141","article-title":"Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis","volume":"204","author":"Nylen","year":"2007","journal-title":"J Exp Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031551","article-title":"Regulatory T cells suppress T cell activation at the pathologic site of human visceral leishmaniasis","volume":"7","author":"Rai","year":"2012","journal-title":"PloS One"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13074","article-title":"T cell suppression in the bone marrow of visceral leishmaniasis patients: impact of parasite load","volume":"191","author":"Kumar","year":"2018","journal-title":"Clin Exp Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.01.020","article-title":"Human FOXP3(+) regulatory T cell heterogeneity and function in autoimmunity and cancer","volume":"50","author":"Wing","year":"2019","journal-title":"Immunity"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.08.012","article-title":"Induced regulatory T cells: their development, stability, and applications","volume":"37","author":"Kanamori","year":"2016","journal-title":"Trends Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12746","article-title":"The Yin and Yang of regulatory T cells in infectious diseases and avenues to target them","volume":"19","author":"Stephen-Victor","year":"2017","journal-title":"Cell Microbiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.146.3.1026","article-title":"Reduction in the number of UCHL-1+ cells and IL-2 production in the peripheral blood of patients with visceral leishmaniasis","volume":"146","author":"Cillari","year":"1991","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases","volume":"155","author":"Sakaguchi","year":"1995","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20060468","article-title":"Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells","volume":"203","author":"Seddiki","year":"2006","journal-title":"J Exp Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001171","article-title":"Foxp3 and IL-10 expression correlates with parasite burden in lesional tissues of post kala azar dermal leishmaniasis (PKDL) patients","volume":"5","author":"Katara","year":"2011","journal-title":"PloS Negl Trop Dis"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200508-1294OC","article-title":"Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis","volume":"173","author":"Guyot-Revol","year":"2006","journal-title":"Am J Respir Crit Care Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2007.06.004","article-title":"In vitro expansion of CD4+CD25highFOXP3+CD127low\/- regulatory T cells from peripheral blood lymphocytes of healthy Mycobacterium tuberculosis-infected humans","volume":"9","author":"Hougardy","year":"2007","journal-title":"Microbes Infect"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.08.006","article-title":"Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection","volume":"23","author":"Walther","year":"2005","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-04-016923","article-title":"Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART","volume":"108","author":"Epple","year":"2006","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-021576","article-title":"HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV\/AIDS","volume":"108","author":"Nilsson","year":"2006","journal-title":"Blood"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-01-0365","article-title":"Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients","volume":"104","author":"Weiss","year":"2004","journal-title":"Blood"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.1.739","article-title":"Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B","volume":"177","author":"Xu","year":"2006","journal-title":"J Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20649","article-title":"Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection","volume":"41","author":"Stoop","year":"2005","journal-title":"Hepatology"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.9.5811","article-title":"Systemic and local characterization of regulatory T cells in a chronic fungal infection in humans","volume":"177","author":"Cavassani","year":"2006","journal-title":"J Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200104)31:4<1122::AID-IMMU1122>3.0.CO;2-P","article-title":"Human anergic\/suppressive CD4(+)CD25(+) T cells: a highly differentiated and apoptosis-prone population","volume":"31","author":"Taams","year":"2001","journal-title":"Eur J Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.2.303","article-title":"Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4","volume":"192","author":"Takahashi","year":"2000","journal-title":"J Exp Med"},{"key":"B50","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1084\/jem.192.2.295","article-title":"Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation","volume":"192","author":"Read","year":"2000","journal-title":"J Exp Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S1286-4579(01)01453-8","article-title":"Control of organ-specific autoimmunity by immunoregulatory CD4(+)CD25(+) T cells","volume":"3","author":"McHugh","year":"2001","journal-title":"Microbes Infect"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.10.5012","article-title":"CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4","volume":"171","author":"Liu","year":"2003","journal-title":"J Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-02-482539","article-title":"Multiparameter single-cell profiling of human CD4+FOXP3+ regulatory T-cell populations in homeostatic conditions and during graft-versus-host disease","volume":"122","author":"Dong","year":"2013","journal-title":"Blood"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1385\/0-89603-062-8:1","article-title":"The lowry method for protein quantitation","volume":"1","author":"Waterborg","year":"1984","journal-title":"Methods Mol Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1676937\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T06:29:59Z","timestamp":1764224999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1676937\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":54,"alternative-id":["10.3389\/fimmu.2025.1676937"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1676937","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]},"article-number":"1676937"}}