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The transforming growth factor receptor III (TβRIII) is commonly recognized as a co-receptor that promotes the binding of TGFβ family ligands to type I and type II receptors. Within the immune system, TβRIII regulates T cell development in the thymus and is differentially expressed through activation; however, its function in mature T cells is unclear. To begin addressing this question, we developed a conditional knock-out mouse with restricted TβRIII deletion in mature T cells, necessary because genomic deletion of TβRIII results in perinatal mortality. We determined that TβRIII null mice developed more severe autoimmune central nervous neuroinflammatory disease after immunization with myelin oligodendrocyte peptide (MOG35-55) than wild-type littermates. The increase in disease severity in TβRIII null mice was associated with expanded numbers of CNS infiltrating IFNγ+ CD4+ T cells and cells that co-express both IFNγ and IL-17 (IFNγ+/IL-17+), but not IL-17 alone expressing CD4 T cells compared to Tgfbr3fl/fl wild-type controls. This led us to speculate that TβRIII may be involved in regulating conversion of encephalitogenic Th17 to Th1. To directly address this, we generated encephalitogenic Th17 and Th1 cells from wild type and TβRIII null mice for passive transfer of EAE into naïve mice. Remarkably, Th17 encephalitogenic T cells from TβRIII null induced EAE of much greater severity and earlier in onset than those from wild-type mice. The severity of EAE induced by encephalitogenic wild-type and Tgfbr3fl/fl.dLcKCre Th1 cells were similar. Moreover, in vitro restimulation of in vivo primed Tgfbr3fl/fl.dLcKCre T cells, under Th17 but not Th1 polarizing conditions, resulted in a significant increase of IFNγ+ T cells. Altogether, our data indicate that TβRIII is a coreceptor that functions as a key checkpoint in controlling the pathogenicity of autoreactive T cells in neuroinflammation probably through regulating plasticity of Th17 T cells into pathogenic Th1 cells. Importantly, this is the first demonstration that TβRIII has an intrinsic role in T cells.

TGF-β receptor 3 (TGFβ-R3), also known as betaglycan, promotes high-affinity binding of TGF-β (1, 2 and 3) to TGFβ-R1 and TGFβ-R2 and is also a receptor for bone morphogenetic proteins (BMP) and inhibins. The embryonic lethality of TGFβ-R3 knock-outs hindered the understanding of its mechanistic function in immune response. To interrogate the function of TGFβ-R3 in mature T cells (T-Tgfbr3KO), we generated a conditional Tgfbr3f/f mouse and bred it with the dLckCre mouse. We found EAE in mice with T-Tgfbr3KO developed with greater severity and mortality than WT littermate mice in both males and females. The onset of disease was similar. The greater severity in T cell T-Tgfbr3KO mice was associated with increased proportion of Th1 cells in the CNS with no difference in numbers of Th17 cells. OT2 T-Tgfbr3KO CD4 T cells also polarized more efficiently to Th1 cells than T-Tgfbr3WT CD4 T cells. The lack of TGF-βR3 had no significant effect on differentiation of Th17 cells. Since our results indicates that TGF-βR3 regulates differentiation to IFN-γ expressing T cells, we interrogated if T-dependent B cells responses to IFN-γ switching will be altered in mice immunized with TNP-KLH. We found that IFN-γ switch dependent anti-TNP IgG2c and IgG3 was greatly enhanced in T-Tgfbr3KO mice compared to WT littermates. All other isotypes were similar in both groups. Our data reveal a novel role for TGFβ-R3 in regulating differentiation of naïve CD4 T cells to IFN-γ expressing cells.

Severe stress leads to alterations in energy metabolism with sexually dimorphic onset or severity. The locus coeruleus (LC) in the brainstem that mediates fight-or-flight-or-freeze response to stress is sexually dimorphic in morphology, plays a key role in interactions between diet and severe stressors, and has neuronal input to the brown adipose tissue (BAT)—a thermogenic organ important for energy balance. Yet, little is known on how LC coordinates stress-related metabolic adaptations. LC expresses receptors for the neuropeptide PACAP (pituitary adenylate cyclase activating peptide) and PACAP signaling through PAC1 (PACAP receptor) are critical regulators of various types of stressors and energy metabolism. We hypothesized that LC-PAC1 axis is a sex-specific central “gatekeeper” of severe acute stress-driven behavior and energy metabolism. Selective ablation of PAC1 receptors from the LC did not alter stress response in mice of either sex, but enhanced food intake in females and was associated with increased energy expenditure and BAT thermogenesis in male mice. These results show a sexually dimorphic role of the LC-PAC1 in regulating acute stress-related energy metabolism. Thus, by disrupting LC-PAC1 signaling, our studies show a unique and previously unexplored role of LC in adaptive energy metabolism in a sex-dependent manner.

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