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Title: The role of toll-like receptor 2 in the function of CD4pos CD25pos regulatory T cells from multiple sclerosis paitents and healthy controls
Author: Nyirenda, Mukanthu Howard
ISNI:       0000 0004 2740 6924
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2012
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Naturally occurring CD4+CD25+FOXP3+ regulatory T cells suppress the activity of pathogenic T cells and prevent development of autoimmune responses. Reduced immunoregulatory activity of Tregs has been reported to increase susceptibility to autoimmune diseases, including multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. An interesting development in the field of innate immune regulation of adaptive T cell responses has been the description of Toll-like receptor (TLR) expression on Tregs. There is growing evidence that TLRs are involved in modulating regulatory T cell (Treg) functions both directly and indirectly. Specifically, TLR2 stimulation has been shown to reduce the suppressive function of Tregs by mechanisms that are incompletely understood. The developmental pathways of Tregs and Th 17 cells are considered divergent and mutually inhibitory, and IL-17 secretion has been reported to be associated with reduced Treg function. The hypothesis was that TLR2 stimulation may reduce the suppressive function of Tregs by regulating the balance between Treg and Th17 phenotype and function. The effect of different TLR2ligands was examined on the suppressive functions of Tregs and found that activation of TLR1I2 heterodimers reduces the suppressive activity of CD4+CD25hiFOXP3IowCD45RA+ (naive) and CD4+CD25hiFOXP3hi CD45RA- (memory or effector) Treg subpopulations on CD4+CD25-FOXP3-CD45RA+ responder T cell proliferation while at the same time enhancing the secretion of IL-6 and IL-17, increasing RORC, and decreasing FOXP3 expression. Neutralization of IL-6 or IL-17 abrogated Pam3Cys-mediated reduction of Treg suppressive function. It was also found that, in agreement with recent observations in mouse T cells, TLR2 stimulation can promote Th17 differentiation of human T helper precursors. Basing on the observation of increased expression of TLR2 by MS patients compared with healthy controls, it was hypothesised that Tregs from MS patients may be more susceptible to TLR2- induced loss of their suppressive functions and differentiation towards a Th17 lineage. It was observed that the suppressive functions of the highly suppressive CD4+CD25hiCD127lo/negFOXP3+ Tregs as well as CD45RA +POXP31ow (naive Tregs) and CD45RA-FOXP3hi (effector Tregs) Treg subsets from MS patients are more susceptible than healthy controls to TLR2-induced reduction of suppressive function and expression of Th17 cytokines. Stimulation of CD4+ T cells with Pam3Cys enhanced the expression of IL-6 and pSTAT3. Blocking TLR2 with a neutralising Ab reduced the expression of IL-6, IL-17 and pSTAT3 induced by Pam3Cys. Together, these data suggest that IL-6/STAT3 signalling is involved in TLR2-mediated reduction of Treg function and Th17 skewing of Tregs, and also in the differentiation of Thl7 cells from naive precursors. The conclusion is that TLR2 stimulation, in combination with TCR activation and eo-stimulation, promotes the differentiation of distinct subsets of human naive and memory/effector Tregs into a Thl7-like phenotype and their expansion. In MS, infections could thus modulate the Treg/Th17 balance with implications for disease activity and progression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available