IL-10-Dependent Suppression of Experimental Allergic Encephalomyelitis by Th2-Differentiated, Anti-TCR Redirected T Lymphocytes

Abstract

We previously showed that transgenically expressed chimeric Ag-MHC-ζ receptors can Ag-specifically redirect T cells against other T cells. When the receptor’s extracellular Ag-MHC domain engages cognate TCR on an Ag-specific T cell, its cytoplasmic ζ-chain stimulates the chimeric receptor-modified T cell (RMTC). This induces effector functions such as cytolysis and cytokine release. RMTC expressing a myelin basic protein (MBP) 89–101-IAs-ζ receptor can be used therapeutically, Ag-specifically treating murine experimental allergic encephalomyelitis (EAE) mediated by MBP89-101-specific T cells. In initial studies, isolated CD8+ RMTC were therapeutically effective whereas CD4+ RMTC were not. We re-examine here the therapeutic potential of CD4+ RMTC. We demonstrate that Th2-differentiated, though not Th1-differentiated, CD4+ MBP89–101-IAs-ζ RMTC prevent actively induced or adoptively transferred EAE, and treat EAE even after antigenic diversification of the pathologic T cell response. The Th2 RMTC both Th2-deviate autoreactive T cells and suppress autoantigen-specific T cell proliferation. IL-10 is critical for the suppressive effects. Anti-IL-10R blocks RMTC-mediated modulation of EAE and suppression of autoantigen proliferation, as well as the induction of IL-10 production by autoreactive T cells. In contrast to IL-10, IL-4 is required for IL-4 production by, and hence Th2 deviation of autoreactive T cells, but not the therapeutic activity of the RMTC. These results therefore demonstrate a novel immunotherapeutic approach for the Ag-specific treatment of autoimmune disease with RMTC. They further identify an essential role for IL-10, rather than Th2-deviation itself, in the therapeutic effectiveness of these redirected Th2 T cells.

IL-10-dependent infectious tolerance after the treatment of experimental allergic encephalomyelitis with redirected CD4+CD25+T lymphocytes

“…Indeed, in a study by Kohm et al (11), suppression of EAE by antigen-nonspecific CD4 ϩ CD25 ϩ regulatory T cells was associated with a Th2 shift among autoreactive lymphocytes. However, in analyses similar to those performed here, we have found that Th2-differentiated RMTC can Th2-deviate the response of autoreactive MBP89-101-specific T lymphocytes (27). This deviation results in greater than four to five times the level of IL-4 production and less than one-third the IL-10 production observed with the use of CD4 ϩ CD25 ϩ RMTC, suggesting that the regulatory cells that we observe here are not exclusively Th2.…”

“…The amount of IL-4 produced was low. Indeed, we have also used Th2-differentiated RMTC to similarly target MBP89-101-specific T cells in vivo, and, when this is done, the MBP89-101-induced IL-4 production is Ϸ5-fold higher than after the use of CD4 ϩ CD25 ϩ RMTC here (27). In contrast to the relatively weak IL-4 production, autoantigen-induced IL-10 production was strongly increased, implying a role for this cytokine in the immunotherapeutic effect.…”

Regulatory T Cell Vaccination without Autoantigen Protects against Experimental Autoimmune Encephalomyelitis

“…Other works have shown that protective T reg cells preferentially produce IL-10 (23, [47][48][49]. Clearly, this was not the case here, although some IL-10 was produced by CD25 Ϫ CD4 ϩ T cells.…”

Mitigation of Experimental Allergic Encephalomyelitis by TGF-β Induced Foxp3+ Regulatory T Lymphocytes through the Induction of Anergy and Infectious Tolerance

“…IL-10 transgenic mice are resistant to EAE, whereas IL-10 Ϫ/Ϫ mice show increased disease severity (44). Th2 T cells ameliorate EAE through IL-10 production (45). CNS IL-10 expression correlates with disease resolution (46).…”