Defective Ca2+ signalling between B cells and regulatory T cells: connecting the dots in the emergence of impaired peripheral B cell tolerance in multiple sclerosis?

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The present proposal intends to advance our understanding of the molecular mechanisms regulating the control of pathogenic B cells in multiple sclerosis (MS), an autoimmune-mediated demyelinating disorder of the central nervous system (CNS). Recent evidence has revealed that an impaired peripheral B cell tolerance accounts for heightened frequencies of pathogenic B cells in patients with MS. This might arise through aberrations in B cell regulation from T cell-independent processes, or through T cell-dependent processes mediated by regulatory T cells (Tregs). Tregs are functionally deficient in patients with MS as we and others have previously shown. Their loss of suppressive properties is precipitated by a contraction of naive cells and reciprocal expansion of memory phenotypes in the peripheral Treg cell compartment, which in turn, possibly arises from premature immunosenescence. At present, little is known as to whether B cells are direct targets of Tregs and how they achieve suppression of B cell effector functions such as immunoglobulin production, antigen presentation, and cytokine secretion. Furthermore, while Modulation of effector T cell responses through B cells is known to occur, the question whether B cells also impact Treg activity has not been addressed. Since any impairment in the bi-directional interaction between the two cell subsets might have harmful consequences on developing autoimmune responses in patients with MS, we aim to analyze the cross-talk between B cells and Tregs in more detail. We intend to employ live Imaging of single cells to measure the capacity of Tregs to modulate Ca2+ signaling in surrounding B cells of various phenotypes, which is a key mechanism utilized by Tregs to confer suppression in conventional T cells (Tcons) as we have previously shown. The imaging experiments will be complemented by assessing the correlation between Ca2+ oscillation patterns and Ca2+-driven downstream events of B cell activation. Complementary experiments aim to clarify whether B cells directly influence the functional capacity of Tregs.