Studies on the differentiation of inflammatory and regulatory T-cells

Jeffery, Louisa Elizabeth (2012). Studies on the differentiation of inflammatory and regulatory T-cells. University of Birmingham. Ph.D.

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Abstract

Low vitamin D is associated with an increased risk of autoimmune diseases, whose pathology might involve T $_R$ $_e$ $_g$ and T $_h$ 17 dysregulation. Thus, understanding how vitamin D modifies CD4 $^+$ T-cell responses holds therapeutic potential. I therefore investigated the effect of 1,25(OH) $_2$ D $_3$ , the active form of vitamin D, upon human CD4 $^+$ T-cell differentiation. 1,25(OH) $_2$ D $_3$ , acted directly upon human CD4 $^+$ T-cells, suppressing inflammatory cytokines (IL-17, IL-21, IFN $_y$ and IL-22) whilst enhancing regulatory markers (CTLA-4, CD25, FoxP3 and IL-10). Consistently, 1,25(OH) $_2$ D $_3$ -treated T-cells suppressed division of naive T-cells stimulated by dendritic cells (DCs). Strong up-regulation of CTLA-4 by 1,25(OH) $_2$ D $_3$ reduced B7 expression by DCs, suggesting that enhanced CTLA-4 could be important mechanistically in 1,25(OH) $_2$ D $_3$ modified immunity. Furthermore, pro-regulatory effects of 1,25(OH) $_2$ D $_3$ were maintained under inflammatory conditions and modest suppression of established IL-17 by 1,25(OH) $_2$ D $_3$ was observed, supporting ability of 1,25(OH) $_2$ D $_3$ to control T-cell phenotype at inflammatory sites. DCs could also efficiently convert 25(OH)D $_3$ to drive 1,25(OH) $_2$ D $_3$ -modified T-cell responses, which might be important in-vivo, given the low level of 1,25(OH) $_2$ D $_3$ in serum. Whether dysregulation of the T $_R$ $_e$ $_g$ /T17 balance or response to 1,25(OH) $_2$ D $_3$ was associated with disease outcome in early synovitis patients was also studied. Although the TReg/T17 ratio did not stratify with outcome, T-cell responses to 1,25(OH) $_2$ D $_3$ were observed in all patients, suggesting that their VDR signalling is intact and that 1,25(OH) $_2$ D $_3$ might be useful in the treatment of synovitis.