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NKG2D is a danger sensor expressed on different subsets of innate and adaptive lymphocytes. Despite its established role as a potent activator of the immune system, NKG2D-driven regulation of CD4+ T helper (Th) cell–mediated immunity remains unclear. In this study, we demonstrate that NKG2D modulates Th1 and proinflammatory T-bet+ Th17 cell effector functions in vitro and in vivo. In particular, NKG2D promotes higher production of proinflammatory cytokines by Th1 and T-bet+ Th17 cells and reinforces their transcription of type 1 signature genes, including Tbx21. Conditional deletion of NKG2D in T cells impairs the ability of antigen-specific CD4+ T cells to promote inflammation in vivo during antigen-induced arthritis and experimental autoimmune encephalomyelitis, indicating that NKG2D is an important target for the amelioration of Th1- and Th17-mediated chronic inflammatory diseases.

Context Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance, and type 2 diabetes, however, the cellular mechanisms are not well understood. Objective This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes. Methods Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 yo, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2 and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify SNPs associated with metabolic traits. Results ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women the expression of ESR1 was higher in VAT than SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake, GLUT4 protein, and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body-fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body-fat percentage. Conclusion E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.