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

Peroxisome proliferator–activated receptors (PPARs; PPAR-α, PPAR-δ, and PPAR-γ) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-δ, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-δ (PPAR-δ−/−) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-γ+IL-17A− and IFN-γ+IL-17A+ CD4+ cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-δ−/− mice occurred as a result of a constellation of immune system aberrations that included higher CD4+ cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-δ in inhibiting the production of IFN-γ and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-δ serves as an important molecular brake for the control of autoimmune inflammation.

Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice.

Peroxisome proliferator-activated receptor (PPAR)-d is a fatty acid-activated transcription factor that regulates metabolic homeostasis, cell growth, and differentiation. Previously, we reported that mice with a global deficiency of PPAR-d develop an exacerbated course of experimental autoimmune encephalomyelitis (EAE), highlighting a role for this nuclear receptor in limiting the development of CNS inflammation. However, the cell-specific contribution of PPAR-d to the more severe CNS inflammatory response remained unclear. In this study, we studied the specific involvement of PPAR-d in myeloid cells during EAE using mice that had Cre-mediated excision of floxed Ppard driven by the lysozyme M (LysM) promoter (LysM Cre :Ppard fl/fl). We observed that LysM Cre :Ppard fl/fl mice were more susceptible to EAE and developed a more severe course of this disease compared with Ppard fl/fl controls. The more severe EAE in LysM Cre :Ppard fl/fl mice was associated with an increased accumulation of pathogenic CD4 + T cells in the CNS and enhanced myelin-specific Th1 and Th17 responses in the periphery. Adoptive transfer EAE studies linked this EAE phenotype in LysM Cre :Ppard fl/fl mice to heightened Th responses. Furthermore, studies using an in vitro CD11b + cell:Th cell coculture system revealed that CD11b + CD11c + dendritic cells (DC) from LysM Cre :Ppard fl/fl mice had a heightened capacity to prime myelin oligodendrocyte glycoprotein (MOG)-specific Th cells compared with Ppard fl/fl counterparts; the effects of DC on Th1 cytokine production were mediated through production of the IL-12p40 homodimer. These studies revealed a role for PPAR-d in DC in limiting Th cell priming during EAE.

Experimental autoimmune encephalomyelitis (EAE) is the most common model of multiple sclerosis (MS). This model has been instrumental in understanding the events that lead to the initiation of central nervous system (CNS) autoimmunity. Though EAE has been an effective screening tool for identifying novel therapies for relapsing-remitting MS, it has proven to be less successful in identifying therapies for progressive forms of this disease. Though axon injury occurs in EAE, it is rapid and acute, making it difficult to intervene for the purpose of evaluating neuroprotective therapies. Here, we describe a variant of spontaneous EAE in the 2D2 T cell receptor transgenic mouse (2D2+ mouse) that presents with hind-limb clasping upon tail suspension and is associated with T cell-mediated inflammation in the posterior spinal cord and spinal nerve roots. Due to the mild nature of clinical signs in this model, we were able to maintain cohorts of mice into middle age. Over 9 mo, these mice exhibited a relapsing-remitting course of hind-limb clasping with the development of progressive motor deficits. Using a combined approach of ex vivo magnetic resonance (MR) imaging and histopathological analysis, we observed neurological progression to associate with spinal cord atrophy, synapse degradation, and neuron loss in the gray matter, as well as ongoing axon injury in the white matter of the spinal cord. These findings suggest that mild EAE coupled with natural aging may be a solution to better modeling the neurodegenerative processes seen in MS.