{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:18:33Z","timestamp":1785403113466,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,9]]},"group-title":"Immunology","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["R01 AI022553, R01 AR040312, R01 AI166313, and P50 AR080594"],"award-info":[{"award-number":["R01 AI022553, R01 AR040312, R01 AI166313, and P50 AR080594"]}]},{"name":"NIH","award":["R01AR048632, R01 AI049313"],"award-info":[{"award-number":["R01AR048632, R01 AI049313"]}]},{"name":"NHMRC Emerging Leadership Investigator Grant","award":["2027104"],"award-info":[{"award-number":["2027104"]}]},{"award":["DP260100848"],"award-info":[{"award-number":["DP260100848"]}],"id":[{"id":"https:\/\/ror.org\/02zp3yd51","id-type":"ROR","asserted-by":"publisher"}]},{"name":"NHMRC investigator award","award":["APP2008981"],"award-info":[{"award-number":["APP2008981"]}]},{"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,9]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Langerhans cells express the nonpolymorphic antigen-presenting molecule CD1a, positioning them as contributors to host immunity against\n                  <jats:italic>Mycobacterium leprae<\/jats:italic>\n                  in human leprosy. CD1a was originally shown to present non-canonical lipopeptide antigens such as dideoxymycobactin and chemically diverse hydrophobic ligands. Here, we generated CD4\u207a T cell lines from leprosy lesions that recognized\n                  <jats:italic>M. leprae<\/jats:italic>\n                  in a CD1a-restricted manner. Unexpectedly, antigen recognition was protease-sensitive, prompting biochemical purification that identified two microbial protein antigens: LppX, a 25-kDa lipoglycoprotein, and Ag85A, a 30-kDa secreted protein with no known lipid modification. Recombinant proteins activated the corresponding T cell lines in a CD1a-dependent manner. Epitope mapping identified 12-mer peptides that fully reconstituted antigenicity, were conserved between\n                  <jats:italic>M. leprae<\/jats:italic>\n                  and\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  , and elicited robust, dose-dependent IFN-\u03b3 production and T cell proliferation, establishing that DNA-encoded, ribosomally translated peptides serve as CD1a-restricted cognate antigens. Biochemical analyses showed peptide binding to CD1a, supported by isoelectric focusing and surface plasmon resonance (\n                  <jats:italic>K<\/jats:italic>\n                  <jats:sub>D<\/jats:sub>\n                  \u223c75 \u03bcM for Ag85A). CD1a\u2013peptide tetramers specifically stained cognate T cells, soluble CD1a was sufficient to present peptide antigen, and transfer of the LppX-specific TCR into na\u00efve T cells restored antigen responsiveness. Using CD1a\u2013peptide tetramers, we identified antigen-specific T cells enriched in patients undergoing reversal reactions compared with patients with lepromatous leprosy and healthy donors. The CD1a-restricted T cell lines secreted IFN-\u03b3 and IL-26, cytokines with established antimicrobial activity. Together, these findings demonstrate that CD1a can present canonical microbial peptides as part of a cell-mediated immune response in leprosy, extending the known spectrum of CD1a ligands. Because CD1a is nonpolymorphic and presents antigens to antimicrobial T cells, CD1a\u2013peptide complexes may provide a broadly applicable platform for studying, detecting, and potentially targeting mycobacterial immunity.\n                <\/jats:p>","DOI":"10.64898\/2026.05.05.723095","type":"posted-content","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T14:05:20Z","timestamp":1778335520000},"source":"Crossref","is-referenced-by-count":0,"title":["CD1a-Mediated Presentation of Canonical Microbial Peptides to T Cells"],"prefix":"10.64898","author":[{"given":"Bruno Jorge","family":"de Andrade Silva","sequence":"first","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda A.","family":"Fischbacher","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Angela M.","family":"Marques","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annaliza","family":"Legaspi","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Shahine","sequence":"additional","affiliation":[{"name":"Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jade","family":"Kollmorgen","sequence":"additional","affiliation":[{"name":"Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Sieling","sequence":"additional","affiliation":[{"name":"NantWorks, LLC, Culver City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Adriano","family":"Matos e Silva","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristofor J.","family":"Webb","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Bradshaw","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Brennan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Marusina","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of California, Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khiem A.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of California, Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euzenir Nunes","family":"Sarno","sequence":"additional","affiliation":[{"name":"Leprosy Laboratory, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta Olmo","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Leprosy Laboratory, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk M.","family":"Zajonc","sequence":"additional","affiliation":[{"name":"Division of Immune Regulation, La Jolla Institute for Immunology, La Jolla, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. Branch","family":"Moody","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayvan R.","family":"Niazi","sequence":"additional","affiliation":[{"name":"NantWorks, LLC, Culver City, California, USA"},{"name":"NanoCav LLC, Culver City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanual","family":"Maverakis","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of California, Davis, Sacramento, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Sette","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USA"},{"name":"Department of Medicine, University of California San Diego, San Diego, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Rossjohn","sequence":"additional","affiliation":[{"name":"Infection and Immunity Program & Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria T.","family":"Ochoa","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Southern California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T.","family":"Belisle","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Modlin","sequence":"additional","affiliation":[{"name":"Division of Dermatology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA"},{"name":"Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026051205100447000_2026.05.05.723095v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0039.1991.tb01836.x"},{"key":"2026051205100447000_2026.05.05.723095v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1089353"},{"key":"2026051205100447000_2026.05.05.723095v1.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.000802"},{"key":"2026051205100447000_2026.05.05.723095v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5336.283"},{"key":"2026051205100447000_2026.05.05.723095v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/372691a0"},{"key":"2026051205100447000_2026.05.05.723095v1.6","doi-asserted-by":"publisher","DOI":"10.1126\/science.7542404"},{"key":"2026051205100447000_2026.05.05.723095v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/35009119"},{"key":"2026051205100447000_2026.05.05.723095v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/nature05907"},{"key":"2026051205100447000_2026.05.05.723095v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13257"},{"key":"2026051205100447000_2026.05.05.723095v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5273.349"},{"key":"2026051205100447000_2026.05.05.723095v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80425-2"},{"key":"2026051205100447000_2026.05.05.723095v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80539-7"},{"key":"2026051205100447000_2026.05.05.723095v1.13","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-121824-071940"},{"key":"2026051205100447000_2026.05.05.723095v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.12.009"},{"key":"2026051205100447000_2026.05.05.723095v1.15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050773"},{"key":"2026051205100447000_2026.05.05.723095v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3523"},{"key":"2026051205100447000_2026.05.05.723095v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2790"},{"key":"2026051205100447000_2026.05.05.723095v1.18","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aax5430"},{"key":"2026051205100447000_2026.05.05.723095v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/ni948"},{"key":"2026051205100447000_2026.05.05.723095v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/S0190-9622(83)70021-6"},{"key":"2026051205100447000_2026.05.05.723095v1.21","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12263574"},{"key":"2026051205100447000_2026.05.05.723095v1.22","first-page":"253","article-title":"Epidermal keratinocyte Ia expression, Langerhans cell hyperplasia and lymphocytic infiltration in skin lesions of leprosy","volume":"65","year":"1986","journal-title":"Clin. 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