Celiac disease (CeD) manifests with autoimmune intestinal inflammation from gluten and genetic predisposition linked to human leukocyte antigen class-II (HLA-II) gene variants. Antigen-presenting cells facilitate gluten exposition through the interaction of their surface major histocompatibility complex (MHC) with the T cell receptor (TCR) on T lymphocytes. This fundamental mechanism of adaptive immunity has broadened upon recognition of extracellular exosomal MHC, raising awareness of an alternative means for antigen presentation. This study demonstrates that conditioned growth media (CGM) previously exposed to monocyte-derived dendritic cells from CeD significantly downregulates the CD3+ lineage marker of control T cells. Such increased activation was reflected in their elevated IL-2 secretion. Exosome localization motif identification and quantification within HLA-DQA1 and HLA-DQB1 transcripts highlighted their significant prevalence within HLA-DQB1 alleles associated with CeD susceptibility. Flow cytometry revealed the strong correlation between HLA-DQ and the CD63 exosomal marker in T cells exposed to CGM from MoDCs sourced from CeD patients. This resulted in lower concentrations of CD25+ CD127- T cells, suggestive of their compromised induction to T-regulatory cells associated with CeD homeostasis. This foremost comparative study deciphered the genomic basis and extracellular exosomal effects of HLA transfer on T lymphocytes in the context of CeD, offering greater insight into this auto-immune disease.

Department of Immunology 3rd Faculty of Medicine Charles University Ruská 87 10000 Prague Czech Republic

Department of Medical Genetics 3rd Faculty of Medicine Charles University Ruská 87 10000 Prague Czech Republic

Faculty of Engineering and Science University of Greenwich London Chatham Maritime Kent ME4 4TB UK

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Maki M., Collin P. Coeliac disease. Lancet. 1997;349:1755–1759. doi: 10.1016/S0140-6736(96)70237-4. PubMed DOI

Marsh M.N. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’) Gastroenterology. 1992;102:330–354. doi: 10.1016/0016-5085(92)91819-P. PubMed DOI

Sollid L.M. Coeliac disease: Dissecting a complex inflammatory disorder. Nat. Rev. Immunol. 2002;2:647–655. doi: 10.1038/nri885. PubMed DOI

Shan L., Molberg Ø., Parrot I., Hausch F., Filiz F., Gray G.M., Sollid L.M., Khosla C. Structural basis for gluten intolerance in celiac sprue. Science. 2002;297:2275–2279. doi: 10.1126/science.1074129. PubMed DOI

Malamut G., Matysiak-Budnik T., Grosdider E., Jais J.-P., Morales E., Damotte D., Caillat-Zucman S., Brousse N., Cerf-Bensussan N., Jian R., et al. Adult celiac disease with severe or partial villous atrophy: A comparative study. Gastroenterol. Clin. Biol. 2008;32:236–242. doi: 10.1016/j.gcb.2008.02.011. PubMed DOI

Visser J., Rozing J., Sapone A., Lammers K., Fasano A. Tight junctions, intestinal permeability, and autoimmunity: Celiac disease and type 1 diabetes paradigms. Ann. N. Y. Acad. Sci. 2009;1165:195–205. doi: 10.1111/j.1749-6632.2009.04037.x. PubMed DOI PMC

Schumann M., Siegmund B., Schulzke J.D., Fromm M. Celiac Disease: Role of the Epithelial Barrier. Cell. Mol. Gastroenterol. Hepatol. 2017;3:150–162. doi: 10.1016/j.jcmgh.2016.12.006. PubMed DOI PMC

Szalowska D., Bak-Romaniszyn L. Family recognition of celiac disease. Prz. Gastroenterol. 2013;8:390–395. doi: 10.5114/pg.2013.39923. PubMed DOI PMC

Lundin K.E., Wijmenga C. Coeliac disease and autoimmune disease-genetic overlap and screening. Nat. Rev. Gastroenterol. Hepatol. 2015;12:507–515. doi: 10.1038/nrgastro.2015.136. PubMed DOI

Hudec M., Riegerova K., Pala J., Kutna V., Cerna M., VB O.L. Celiac Disease Defined by Over-Sensitivity to Gliadin Activation and Superior Antigen Presentation of Dendritic Cells. Int. J. Mol. Sci. 2021;22:9982. doi: 10.3390/ijms22189982. PubMed DOI PMC

Lebwohl B., Sanders D.S., Green P.H.R. Coeliac disease. Lancet. 2018;391:70–81. doi: 10.1016/S0140-6736(17)31796-8. PubMed DOI

Zajacova M., Kotrbova-Kozak A., Cerna M. HLA-DRB1, -DQA1 and -DQB1 genotyping of 180 Czech individuals from the Czech Republic pop 3. Hum. Immunol. 2016;77:365–366. doi: 10.1016/j.humimm.2016.02.003. PubMed DOI

Laupeze B., Fardel O., Onno M., Bertho N., Drenou B., Fauchet R., Amiot L. Differential expression of major histocompatibility complex class Ia, Ib, and II molecules on monocytes-derived dendritic and macrophagic cells. Hum. Immunol. 1999;60:591–597. doi: 10.1016/S0198-8859(99)00025-7. PubMed DOI

Nouri-Shirazi M., Banchereau J., Bell D., Burkeholder S., Kraus E.T., Davoust J., Palucka K.A. Dendritic cells capture killed tumor cells and present their antigens to elicit tumor-specific immune responses. J. Immunol. 2000;165:3797–3803. doi: 10.4049/jimmunol.165.7.3797. PubMed DOI

Palova-Jelinkova L., Rozkova D., Pecharova B., Bartova J., Sediva A., Tlaskalova-Hogenova H., Spisek R., Tuckova L. Gliadin fragments induce phenotypic and functional maturation of human dendritic cells. J. Immunol. 2005;175:7038–7045. doi: 10.4049/jimmunol.175.10.7038. PubMed DOI

Raki M., Tollefsen S., Molberg O., Lundin K.E., Sollid L.M., Jahnsen F.L. A unique dendritic cell subset accumulates in the celiac lesion and efficiently activates gluten-reactive T cells. Gastroenterology. 2006;131:428–438. doi: 10.1053/j.gastro.2006.06.002. PubMed DOI

Raposo G., Nijman H.W., Stoorvogel W., Liejendekker R., Harding C.V., Melief C.J., Geuze H.J. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 1996;183:1161–1172. doi: 10.1084/jem.183.3.1161. PubMed DOI PMC

Thery C., Boussac M., Veron P., Ricciardi-Castagnoli P., Raposo G., Garin J., Amigorena S. Proteomic analysis of dendritic cell-derived exosomes: A secreted subcellular compartment distinct from apoptotic vesicles. J. Immunol. 2001;166:7309–7318. doi: 10.4049/jimmunol.166.12.7309. PubMed DOI

Wubbolts R., Leckie R.S., Veenhuizen P.T., Schwarzmann G., Mobius W., Hoernschemeyer J., Slot J.W., Geuze H.J., Stoorvogel W. Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation. J. Biol. Chem. 2003;278:10963–10972. doi: 10.1074/jbc.M207550200. PubMed DOI

Buschow S.I., Nolte-’t Hoen E.N., van Niel G., Pols M.S., ten Broeke T., Lauwen M., Ossendorp F., Melief C.J., Raposo G., Wubbolts R., et al. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic. 2009;10:1528–1542. doi: 10.1111/j.1600-0854.2009.00963.x. PubMed DOI

Nolte-’t Hoen E.N., Buschow S.I., Anderton S.M., Stoorvogel W., Wauben M.H. Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood. 2009;113:1977–1981. doi: 10.1182/blood-2008-08-174094. PubMed DOI

Zitvogel L., Regnault A., Lozier A., Wolfers J., Flament C., Tenza D., Ricciardi-Castagnoli P., Raposo G., Amigorena S. Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes. Nat. Med. 1998;4:594–600. doi: 10.1038/nm0598-594. PubMed DOI

Kowal J., Arras G., Colombo M., Jouve M., Morath J.P., Primdal-Bengtson B., Dingli F., Loew D., Tkach M., Thery C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc. Natl. Acad. Sci. USA. 2016;113:E968–E977. doi: 10.1073/pnas.1521230113. PubMed DOI PMC

Kanamori M., Nakatsukasa H., Okada M., Lu Q., Yoshimura A. Induced Regulatory T Cells: Their Development, Stability, and Applications. Trends Immunol. 2016;37:803–811. doi: 10.1016/j.it.2016.08.012. PubMed DOI

Longhi M.S., Ma Y., Bogdanos D.P., Cheeseman P., Mieli-Vergani G., Vergani D. Impairment of CD4(+)CD25(+) regulatory T cells in autoimmune liver disease. J. Hepatol. 2004;41:31–37. doi: 10.1016/j.jhep.2004.03.008. PubMed DOI

Kumar V., Sercarz E. An integrative model of regulation centered on recognition of TCR peptide/MHC complexes. Immunol. Rev. 2001;182:113–121. doi: 10.1034/j.1600-065X.2001.1820109.x. PubMed DOI

Gurunathan S., Kang M.H., Jeyaraj M., Qasim M., Kim J.H. Review of the Isolation, Characterization, Biological Function, and Multifarious Therapeutic Approaches of Exosomes. Cells. 2019;8:307. doi: 10.3390/cells8040307. PubMed DOI PMC

Munich S., Sobo-Vujanovic A., Buchser W.J., Beer-Stolz D., Vujanovic N.L. Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands. Oncoimmunology. 2012;1:1074–1083. doi: 10.4161/onci.20897. PubMed DOI PMC

Batagov A.O., Kuznetsov V.A., Kurochkin I.V. Identification of nucleotide patterns enriched in secreted RNAs as putative cis-acting elements targeting them to exosome nano-vesicles. BMC Genom. 2011;12((Suppl. 3)):S18. doi: 10.1186/1471-2164-12-S3-S18. PubMed DOI PMC

O’Leary V.B., Ovsepian S.V., Carrascosa L.G., Buske F.A., Radulovic V., Niyazi M., Moertl S., Trau M., Atkinson M.J., Anastasov N. PARTICLE, a Triplex-Forming Long ncRNA, Regulates Locus-Specific Methylation in Response to Low-Dose Irradiation. Cell Rep. 2015;11:474–485. doi: 10.1016/j.celrep.2015.03.043. PubMed DOI

Maccari G., Robinson J., Hammond J.A., Marsh S.G.E. The IPD Project: A centralised resource for the study of polymorphism in genes of the immune system. Immunogenetics. 2020;72:49–55. doi: 10.1007/s00251-019-01133-w. PubMed DOI PMC

Kovacs A.A.Z., Kono N., Wang C.H., Wang D., Frederick T., Operskalski E., Tien P.C., French A.L., Minkoff H., Kassaye S., et al. Association of HLA Genotype With T cell Activation in Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus-Coinfected Women. J. Infect. Dis. 2020;221:1156–1166. doi: 10.1093/infdis/jiz589. PubMed DOI PMC

Kondelkova K., Vokurkova D., Krejsek J., Borska L., Fiala Z., Ctirad A. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Medica. 2010;53:73–77. doi: 10.14712/18059694.2016.63. PubMed DOI

Guo J., Zhou X. Regulatory T cells turn pathogenic. Cell. Mol. Immunol. 2015;12:525–532. doi: 10.1038/cmi.2015.12. PubMed DOI PMC

Zheng S.G., Gray J.D., Ohtsuka K., Yamagiwa S., Horwitz D.A. Generation ex vivo of TGF-beta-producing regulatory T cells from CD4+CD25- precursors. J. Immunol. 2002;169:4183–4189. doi: 10.4049/jimmunol.169.8.4183. PubMed DOI

Takahashi T., Tagami T., Yamazaki S., Uede T., Shimizu J., Sakaguchi N., Mak T.W., Sakaguchi S. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 2000;192:303–310. doi: 10.1084/jem.192.2.303. PubMed DOI PMC

Gaudino S.J., Kumar P. Cross-Talk Between Antigen Presenting Cells and T Cells Impacts Intestinal Homeostasis, Bacterial Infections, and Tumorigenesis. Front. Immunol. 2019;10:360. doi: 10.3389/fimmu.2019.00360. PubMed DOI PMC

Turley S.J., Inaba K., Garrett W.S., Ebersold M., Unternaehrer J., Steinman R.M., Mellman I. Transport of peptide-MHC class II complexes in developing dendritic cells. Science. 2000;288:522–527. doi: 10.1126/science.288.5465.522. PubMed DOI

Robins G., Howdle P.D. Advances in celiac disease. Curr. Opin. Gastroenterol. 2005;21:152–161. doi: 10.1097/01.mog.0000153312.05457.8d. PubMed DOI

Perez-Bravo F., Araya M., Mondragon A., Rios G., Alarcon T., Roessler J.L., Santos J.L. Genetic differences in HLA-DQA1* and DQB1* allelic distributions between celiac and control children in Santiago, Chile. Hum. Immunol. 1999;60:262–267. doi: 10.1016/S0198-8859(98)00119-0. PubMed DOI

Shevach E.M. CD4+ CD25+ suppressor T cells: More questions than answers. Nat. Rev. Immunol. 2002;2:389–400. doi: 10.1038/nri821. PubMed DOI

Hadis U., Wahl B., Schulz O., Hardtke-Wolenski M., Schippers A., Wagner N., Muller W., Sparwasser T., Forster R., Pabst O. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity. 2011;34:237–246. doi: 10.1016/j.immuni.2011.01.016. PubMed DOI

Josefowicz S.Z., Niec R.E., Kim H.Y., Treuting P., Chinen T., Zheng Y., Umetsu D.T., Rudensky A.Y. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature. 2012;482:395–399. doi: 10.1038/nature10772. PubMed DOI PMC

Dominguez-Villar M., Hafler D.A. Regulatory T cells in autoimmune disease. Nat. Immunol. 2018;19:665–673. doi: 10.1038/s41590-018-0120-4. PubMed DOI PMC

Liu H., Leung B.P. CD4+CD25+ regulatory T cells in health and disease. Clin. Exp. Pharmacol. Physiol. 2006;33:519–524. doi: 10.1111/j.1440-1681.2006.04401.x. PubMed DOI

Husby S., Koletzko S., Korponay-Szabo I., Kurppa K., Mearin M.L., Ribes-Koninckx C., Shamir R., Troncone R., Auricchio R., Castillejo G., et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J. Pediatr. Gastroenterol. Nutr. 2020;70:141–156. doi: 10.1097/MPG.0000000000002497. PubMed DOI

Robinson J., Halliwell J.A., McWilliam H., Lopez R., Marsh S.G. IPD—The Immuno Polymorphism Database. Nucleic Acids Res. 2013;41:D1234–D1240. doi: 10.1093/nar/gks1140. PubMed DOI PMC

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