IL-1R and MyD88 signaling in CD4+ T cells promote Th17 immunity and atherosclerosis.

Aims The role of CD4(+) T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4(+) T cells in atherosclerosis. Methods and results We transferred apoe(-/-)myd88(+/+) or apoe(-/-)myd88(-/-) CD4(+) T cells to T- and B-cell-deficient rag1(-/-)apoe(-/-) mice fed high fat diet. Mice given apoe(-/-)myd88(-/-) CD4(+) T cells exhibited reduced atherosclerosis compared with mice given apoe(-/-)myd88(+/+) CD4(+) T cells. CD4(+) T cells from apoe(-/-)myd88(-/-) produced less IL-17 but similar levels of IFN-gamma. Treatment of human CD4(+) T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1(-/-) CD4(+) T cells recapitulated the phenotype seen by transfer of myd88(-/-) CD4(+) T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4(+) T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1(-/-) CD4(+) T cells. Conclusion We demonstrate that both IL-1R and MyD88 signalling in CD4(+) T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels.