Melatonin in Th17/Treg differentiation: the contribution of the hormone's own production by T lymphocytes

The hormone melatonin is involved in regulation of functioning of almost all organs and systems of the organism. In the immune system, T lymphocytes are an important target of melatonin: they express specific melatonin receptors with different affinities – membrane MT1 and MT2 and nuclear RORa, as well as intracellular molecules that nonspecifically bind melatonin at high concentrations. Moreover, many in vitro studies reveal their own production of melatonin by T lymphocytes in response to polyclonal activation and its involvement as autocrine or paracrine factor in the induction of IL-2 and IL-2 receptor (IL-2R) synthesis by T cells, with melatonin receptors involvement in implementation of these effects. Since IL-2/IL-2R-dependent signal is a key event in T lymphocytes proliferative response induction, intrinsic melatonin seems to be directly involved at least in the clonal expansion of these cells. In this work, we investigated the contribution of T cells’ melatonin to regulation of the next stage of T lymphocyte activation, namely, the differentiation of T helper populations Th17 and Treg. It was shown that blockade of both membrane and nuclear melatonin receptors did not cause statistically significant changes in Th17 differentiation, although the trend was fixed for a decrease. Simultaneously, CD4⁺FoxP3⁺Т cells level decreased under the nonselective blockade of membrane hormone receptors, and Treg-associated cytokine TGF-b concentration in activated cultures supernatants decreased both in case of MT1/MT2 nonselective blockade and MT2 selective blockade. The data indicate that melatonin produced by T lymphocytes in culture can contribute to the control of naive CD4⁺T cell differentiation into Treg in vitro, and the hormone effects are mediated by membrane melatonin receptors. The presence of a large number targets with different affinities for melatonin in T lymphocytes determines the key role of the hormone concentration in its effects on these cells. And when interpreting data on melatonin-dependent regulation of Treg, it is important to take into account the hormone’s own production by lymphocytes, since T cells’ melatonin can mask the exogenous hormone effects or interfere with its action due to competitive binding to hormone receptors.

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