The T cell response to IL-10 alters cellular dynamics and paradoxically promotes central nervous system autoimmunity.
IL-10 is a critical anti-inflammatory cytokine, the deficiency of which leads to spontaneous autoimmunity. However, therapeutically administered or ectopically expressed IL-10 can either suppress or promote disease. Distinct lineage-specific activities may explain the contradictory effects of IL-10. To dissect the T cell-specific response to IL-10 during organ-specific autoimmunity, we generated mice with a selective deletion of IL-10Rα in T cells and analyzed its effects in an autoimmune model, experimental allergic encephalomyelitis (EAE). Surprisingly, the T cell response to IL-10 increased EAE severity. This did not result from altered T cell functional potential; T cell cytokine profile was preserved. IL-10 also diminished the proliferation of T cells in situ within the target organ, an effect that would be expected to restrain disease. However, IL-10 acted cell autonomously to sustain the autoreactive T cells essential for immunopathogenesis, promoting their accumulation and distorting the regulatory and effector T cell balance. Indeed, in chimeric mice and after adoptive transfer, wild type T cells showed a competitive advantage over cells deficient in IL-10Rα. Therefore, T cell specific actions of IL-10 can support autoimmune inflammation, and this appears to result from an overall increase in the long term fitness of pathologic T cells. Lineage-restricted, disease-promoting activities of IL-10 should be considered in the therapeutic manipulation of the IL-10 pathway.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38120, USA.
Xin
X
Liu
Rajshekhar
R
Alli
Meredith
M
Steeves
Phuong
P
Nguyen
Peter
P
Vogel
Terrence L
TL
Geiger
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000502:physiology; D016753:Interleukin-10 / Q000008:administration & dosage / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D053701:Receptors, Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D053701:Receptors, Interleukin-10; D016753:Interleukin-10