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.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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