Autoantigen-specific IL-10-transduced T cells suppress chronic arthritis by promoting the endogenous regulatory IL-10 response.
Deficient T cell regulation can be mechanistically associated with development of chronic autoimmune diseases. Therefore, combining the regulatory properties of IL-10 and the specificity of autoreactive CD4(+) T cells through adoptive cellular gene transfer of IL-10 via autoantigen-specific CD4(+) T cells seems an attractive approach to correct such deficient T cell regulation that avoids the risks of nonspecific immunosuppressive drugs. In this study, we studied how cartilage proteoglycan-specific CD4(+) T cells transduced with an active IL-10 gene (T(IL-10)) may contribute to the amelioration of chronic and progressive proteoglycan-induced arthritis in BALB/c mice. TCR-transgenic proteoglycan-specific T(IL-10) cells ameliorated arthritis, whereas T(IL-10) cells with specificity for OVA had no effect, showing the impact of Ag-specific targeting of inflammation. Furthermore, proteoglycan-specific T(IL-10) cells suppressed autoreactive proinflammatory T and B cells, as T(IL-10) cells caused a reduced expression of IL-2, TNF-alpha, and IL-17 and a diminished proteoglycan-specific IgG2a Ab response. Moreover, proteoglycan-specific T(IL-10) cells promoted IL-10 expression in recipients but did not ameliorate arthritis in IL-10-deficient mice, indicating that T(IL-10) cells suppress inflammation by propagating the endogenous regulatory IL-10 response in treated recipients. This is the first demonstration that such targeted suppression of proinflammatory lymphocyte responses in chronic autoimmunity by IL-10-transduced T cells specific for a natural Ag can occur via the endogenous regulatory IL-10 response.
Guichelaar
Teun
T
Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, Utrecht, The Netherlands.
ten Brink
Corlinda B
CB
van Kooten
Peter J
PJ
Berlo
Suzanne E
SE
Broeren
Chris P
CP
van Eden
Willem
W
Broere
Femke
F
D019264:Adoptive Transfer; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000628:therapy*; D001324:Autoantigens / Q000032:analysis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D002356:Cartilage / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011509:Proteoglycans / Q000032:analysis / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
D001324:Autoantigens; D016207:Cytokines; D007074:Immunoglobulin G; D011509:Proteoglycans; D016753:Interleukin-10