In vitro induction of CD25+ CD4+ regulatory T cells by the neuropeptide alpha‐melanocyte stimulating hormone (α‐MSH)

Abstract

Recently, we have found that the neuropeptide alpha‐melanocyte stimulating hormone (α‐MSH) not only suppresses IFN‐γ production, but also induces TGF‐β1 production by activated effector T cells. These α‐MSH‐ treated effector T cells function as regulatory T cells in that they suppress IFN‐γ production and hypersensitivity mediated by other effector T cells. Experimental autoimmune uveoretinitis (EAU) was suppressed in its severity and incidence in mice that were injected with primed T cells activated in vitro by APC and antigen in the presence of α‐MSH. Moreover, it appeared that α‐MSH had converted a population of effector T cells polarized to mediate hypersensitivity into a population of T cells that now mediated immunoregulation. To characterize these α‐MSH‐ treated T cells, primed T cells were TCR‐stimulated in the presence of α‐MSH in vitro and their lymphokine profile was examined. Such effector T cells displayed enhanced levels of TGF‐β1 production and no IFN‐γ or IL‐10, with IL‐4 levels remaining unchanged in comparison with inactivated T cells. In addition, if soluble TGF‐β receptor II was added to cocultures of α‐MSH‐treated T cells and activated Th1 cells, the α‐MSH‐treated T cells could not suppress IFN‐γ production by the Th1 cells. These results suggest that α‐MSH induces T cells with a regulatory lymphokine pattern, and that through their production of TGF‐β1 these cells suppress other effector T cells. Examination of the α‐MSH‐treated T cells showed that α‐MSH did not alter the phosphorylation of CD3 molecules following TCR engagement. Primed T cells express the melanocortin 5 receptor (MC5r), a receptor that is linked to an intracellular signalling pathway shared by other cytokine receptors. Blocking the receptor with antibody prevented α‐MSH from suppressing IFN‐γ production by the activated regulatory T cells, suggesting that α‐MSH immunoregulation is through the MC5r on primed T cells. Surface staining and cell sorting of the α‐MSH‐ treated primed T cells showed that the regulatory T cells are CD25+ CD4+ T cells. From these results we find that α‐MSH can mediate the induction of CD25+ CD4+ regulatory T cells. These regulatory T cells require specific antigen for activation, but through non‐specific TGF‐β1‐mediated mechanisms they can suppress other effector T cells.

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