Endogenous IRBP can be dispensable for generation of natural CD4+CD25+ regulatory T cells that protect from IRBP-induced retinal autoimmunity.
Susceptibility to experimental autoimmune uveitis (EAU), a model for human uveitis induced in mice with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP), is controlled by "natural" CD4+CD25+ regulatory T (T reg) cells. To examine whether endogenous expression of IRBP is necessary to generate these T reg cells, we studied responses of IRBP knockout (KO) versus wild-type (WT) mice. Unexpectedly, not only WT but also IRBP KO mice immunized with a uveitogenic regimen of IRBP in complete Freund's adjuvant (CFA) exhibited CD25+ regulatory cells that could be depleted by PC61 treatment, which suppressed development of uveitogenic effector T cells and decreased immunological responses to IRBP. These EAU-relevant T reg cells were not IRBP specific, as their activity was not present in IRBP KO mice immunized with IRBP in incomplete Freund's adjuvant (IFA), lacking mycobacteria (whereas the same mice exhibited normal T reg cell activity to retinal arrestin in IFA). We propose that mycobacterial components in CFA activate T reg cells of other specificities to inhibit generation of IRBP-specific effector T cells in a bystander fashion, indicating that effective T reg cells can be antigen nonspecific. Our data also provide the first evidence that generation of specific T reg cells to a native autoantigen in a mouse with a diverse T cell repertoire requires a cognate interaction.
Laboratory of Immunology, National Eye Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Rafael S
RS
Grajewski
Phyllis B
PB
Silver
Rajeev K
RK
Agarwal
Shao-Bo
SB
Su
Chi-Chao
CC
Chan
Gregory I
GI
Liou
Rachel R
RR
Caspi
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D015704:CD4 Antigens / Q000096:biosynthesis; D002417:Cattle; D002454:Cell Differentiation / Q000276:immunology*; D005136:Eye Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000172:deficiency; D012160:Retina / Q000276:immunology* / Q000473:pathology; D012177:Retinol-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014605:Uveitis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
D015704:CD4 Antigens; D005136:Eye Proteins; D015375:Receptors, Interleukin-2; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial