Molecular mechanisms of adenosine regulation of helper T cell responses
Embargo Lift Date: 2020-06-05
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Polarizations of helper T cells into different functional subsets is important in order to influence the progression of immune-related diseases. One of the major outcomes in immune cell activation and generation of immunogenic response followed by TCR stimulation, is elevation of extracellular adenosine and upregulation of adenosine A2A receptors. Adenosine A2A receptor stimulation elevates intracellular cAMP to regulate helper T cell responses., Intracellular receptors of cAMP, PKA and EPAC proteins regulate cellular responses downstream of cAMP. In this study, we showed that adenosine differentially suppresses Th1 polarization rather than polarization of other functional T cell subsets. Adenosine signaling strongly decreased T cell accumulation in all the polarizing conditions except for Th2 condition. Adenosine-mediated decrease in T cell accumulation is associated with decreased proliferation and survival. PI3K-AKT pathway by targeting the Akt phospho-activation is one of the essential factors for regulation of immune response. One of the targets for Akt is Foxo1, which is inhibited by Akt phosphorylation. Foxo1 is known to suppress T cell proliferation and important in T cell trafficking and survival. Mechanistic studies have shown that adenosine signaling decreases the phosphorylation of Akt and Foxo1 molecules downstream of TCR. A Foxo1 inhibitor, AS1842856, reverses the reduction in T cell accumulation after adenosine receptor stimulation in particularly Th1 and Th17 conditions by increasing T cell survival in these conditions rather than T cell proliferation. Further studies using PKA and EPAC specific analogs indicated that both pathways may be required for adenosine mediated suppression of Th1 polarization; however, PKA pathway alone is largely responsible from inhibition of T cell proliferation. Results of this study have major implications to understand potential cell-intrinsic effects of one of the major immunoregulatory pathways.