H2A- and H2E-derived CD4+CD25+ regulatory T cells: a potential role in reciprocal inhibition by class II genes in autoimmune thyroiditis.
We recently described a novel H2E class II-transgenic model (A(-)E(+)) of experimental autoimmune thyroiditis (EAT) that permits disease induction with heterologous thyroglobulin (Tg), but unlike conventional susceptible strains, precludes self-reactivity to autologous mouse Tg. In transgenic E(+)B10 (A(+)E(+)) mice, the presence of endogenous H2A genes is protective against H2E-mediated thyroiditis, inhibiting EAT development. The suppressive effect of H2A genes on H2E-mediated thyroiditis mirrors previous reports of H2E suppression on H2A-mediated autoimmune diseases, including EAT. The mechanism of the reciprocal-suppressive effect between class II genes is unclear, although the involvement of regulatory T cells has been proposed. We have recently reported that CD4(+)CD25(+) regulatory T cells mediate peripheral tolerance induced with mouse Tg in CBA mice. To determine whether these cells play a role in our E(+)-transgenic model, we first confirmed the existence of CD4(+)CD25(+) T cells regulating thyroiditis in E(+)B10.Ab(0) (A(-)E(+)) and B10 (A(+)E(-)) mice by i.v. administration of CD25 mAb before EAT induction. The depletion of CD4(+)CD25(+) T cells enhanced thyroiditis induction in the context of either H2E or H2A. Moreover, reconstitution of CD4(+)CD25(+) T cells from naive B10 mice restored resistance to EAT. E(+)B10 (A(+)E(+)) mice were also depleted of CD4(+)CD25(+) T cells before the challenge to determine their role in thyroiditis in the presence of both H2A and H2E genes. Depletion of CD4(+)CD25(+) regulatory T cells offset the suppression of H2E-mediated thyroiditis by H2A. Thus, these regulatory T cells may be involved in the reciprocal-suppressive effect between class II genes.
Morris
Gerald P
GP
Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Yan
Yan
Y
David
Chella S
CS
Kong
Yi-Chi M
YC
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D005802:Genes, MHC Class II / Q000502:physiology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008212:Lymphocyte Depletion / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D013045:Species Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D013954:Thyroglobulin / Q000008:administration & dosage; D013967:Thyroiditis, Autoimmune / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*
D000911:Antibodies, Monoclonal; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D015375:Receptors, Interleukin-2; D013954:Thyroglobulin