The T cell response to interleukin 10 alters cellular dynamics and paradoxically promotes CNS autoimmunity

摘要

IL10 is a critical anti-inflammatory cytokine, deficiency of which leads to spontaneous autoimmunity. Yet therapeutically administered or ectopically expressed IL10 may either suppress or promote disease. Distinct lineage-specific activities may explain IL10’s contradictory effects. To dissect the T cell-specific response to IL10 during organ-specific autoimmunity, we generated mice with a selective deletion of IL10Rα in T cells and analyzed its impact in an autoimmune model, experimental allergic encephalomyelitis (EAE). Surprisingly, the T-cell response to IL10 increased EAE severity. This did not result from altered T cell functional potential; T cell cytokine profile was preserved. IL10 also diminished the proliferation of T cells in situ within the target organ, an effect that would be expected to restrain disease. However, IL10 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 IL10Rα. Therefore T cell specific actions of IL10 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 IL10 should be considered in the therapeutic manipulation of the IL10 pathway.