Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way
- 30 May 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (24), 9505-9510
- https://doi.org/10.1073/pnas.1118458109
Abstract
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.Keywords
This publication has 36 references indexed in Scilit:
- Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosisNature, 2011
- Th1 versus Th17: Are T cell cytokines relevant in multiple sclerosis?Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2011
- T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγtNature Immunology, 2010
- Regulation of the Ifng locus in the context of T‐lineage specification and plasticityImmunological Reviews, 2010
- Sex‐ and Depot‐Dependent Differences in Adipogenesis in Normal‐Weight HumansObesity, 2010
- T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitisNature Medicine, 2010
- The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell–intrinsic fashion and suppresses CNS autoimmunityThe Journal of Experimental Medicine, 2009
- Epigenetics and T helper 1 differentiationImmunology, 2009
- Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cellsNature Immunology, 2007
- Peroxisome proliferator–activated receptor (PPAR)α expression in T cells mediates gender differences in development of T cell–mediated autoimmunityThe Journal of Experimental Medicine, 2007