Women develop certain autoimmune diseases more often than men. It has been hypothesized that this may relate to the development of more robust T-helper (Th)1 responses in women. To test whether women exhibit a Th1 bias, we isolated naïve cluster of differentiation (CD)4 + T cells from peripheral blood of healthy women and men and measured the proliferation and cytokine production by these cells in response to submaximal amounts of anti-CD3 and anti-CD28. We observed that CD4 + T cells from women produced higher levels of IFNγ as well as tended to proliferate more than male CD4 + T cells. Intriguingly, male CD4 + T cells instead had a predilection toward IL-17A production. This sex dichotomy in Th cytokine production was found to be even more striking in the Swiss/Jackson Laboratory (SJL) mouse. Studies in mice and humans indicated that the sexual dimorphism in Th1 and Th17 cytokine production was dependent on the androgen status and the T-cell expression of peroxisome proliferator activated receptor (PPAR)α and PPARγ. Androgens increased PPARα and decreased PPARγ expression by human CD4 + T cells. PPARα siRNA-mediated knockdown had the effect of increasing IFNγ by male CD4 + T cells, while transfection of CD4 + T cells with PPARγ siRNAs increased IL-17A production uniquely by female T cells. Together, our observations indicate that human T cells exhibit a sex difference in the production of IFNγ and IL-17A that may be driven by expressions of PPARα and PPARγ. autoimmunity | cytokines | experimental autoimmune encephalomyelitis | gender | nuclear receptor
Studies suggest T cells modulate arterial pressure. Since robust sex differences exist in the immune system and in hypertension, we investigated sex differences in T cell modulation of angiotensin II (Ang II)-induced increases in mean arterial pressure (MAP) in male (M) and female (F) wild type (WT) and recombination-activating-gene-1-deficient (Rag1−/−) mice. Sex-differences in peak MAP in WT were lost in Rag1−/− mice [mmHg: WT-F, 136±4.9 vs. WT-M, 153±1.7; P<0.02; Rag1−/−-F, 135±2.1 vs. Rag1−/−-M, 141±3.8]. Peak MAP was 13 mmHg higher after adoptive transfer of male (CD3M→Rag1−/−-M) vs. female (CD3F→Rag1−/−-M) T-cells. CD3M→Rag1−/−-M mice exhibited higher splenic frequencies of pro-inflammatory interleukin-17A (2.4-fold) and tumor-necrosis factor-α (2.2-fold)-producing T cells and lower plasma levels (13-fold) and renal mRNA expression (2.4-fold) of interleukin-10 while CD3F→Rag1−/−-M mice displayed a higher activation state in general and T-helper 1-biased renal inflammation. Greater T cell infiltration into perivascular adipose tissue and kidney associated with increased pressor responses to Ang II if the T cell donor was male but not female and these sex differences in T cell subset expansion and tissue infiltration were maintained for 7–8 weeks within the male host. Thus, the adaptive immune response and role of pro- and anti-inflammatory cytokine signaling in hypertension is distinct between the sexes and needs to be understood to improve therapeutics for hypertension-associated disease in both men and women.
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