Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 24, Pages 9505-9510Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1118458109
Keywords
autoimmunity; cytokines; experimental autoimmune encephalomyelitis; gender; nuclear receptor
Categories
Funding
- Canadian Institute of Health Research (CIHR)
- Multiple Sclerosis Society of Canada (MSSC)
- Donald Paty Career Development Awards
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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 nave 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 IFN gamma 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)alpha and PPAR gamma. Androgens increased PPAR alpha and decreased PPAR gamma expression by human CD4(+) T cells. PPAR alpha siRNA-mediated knockdown had the effect of increasing IFN gamma by male CD4(+) T cells, while transfection of CD4(+) T cells with PPAR gamma 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 IFN gamma and IL-17A that may be driven by expressions of PPAR alpha and PPAR gamma.
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