Staphylococcus aureus is the most common cause of skin and soft tissue infections, and rapidly emerging antibiotic-resistant strains are creating a serious public health concern. If immune-based therapies are to be an alternative to antibiotics, greater understanding is needed of the protective immune response against S. aureus infection in the skin. Although neutrophil recruitment is required for immunity against S. aureus, a role for T cells has been suggested. Here, we used a mouse model of S. aureus cutaneous infection to investigate the contribution of T cells to host defense. We found that mice deficient in γδ but not αβ T cells had substantially larger skin lesions with higher bacterial counts and impaired neutrophil recruitment compared with WT mice. This neutrophil recruitment was dependent upon epidermal Vγ5 + γδ T cell production of IL-17, but not IL-21 and IL-22. Furthermore, IL-17 induction required IL-1, TLR2, and IL-23 and was critical for host defense, since IL-17R-deficient mice had a phenotype similar to that of γδ T cell-deficient mice. Importantly, γδ T cell-deficient mice inoculated with S. aureus and treated with a single dose of recombinant IL-17 had lesion sizes and bacterial counts resembling those of WT mice, demonstrating that IL-17 could restore the impaired immunity in these mice. Our study defines what we believe to be a novel role for IL-17-producing epidermal γδ T cells in innate immunity against S. aureus cutaneous infection.

The transient actions of gonadal steroids on the adult brain facilitate social behaviors, including reproduction. In male rodents, testosterone acts in the posterior medial amygdala (MeP) and medial preoptic area (MPOA) to promote mating. Adult neurogenesis occurs in both regions. The current study determined if testosterone and/or sexual behavior promote cell proliferation and survival in MeP and MPOA. Two experiments were conducted using the thymidine analog BrdU. First, gonadintact and castrated male hamsters (n=6/group) were compared 24 hours or 7 weeks after BrdU. In MeP, testosterone stimulated cell proliferation 24 hours after BrdU (intact: 22.8±3.9 cells/mm 2 , castrate: 13.2±1.4cells/mm 2 ). Testosterone did not promote cell proliferation in MPOA. Seven weeks after BrdU, cell survival was sparse in both regions (MeP: 2.5±0.6 and MPOA: 1.7±0.2 cells/mm 2 ), and was not enhanced by testosterone. In Experiment 2, gonad-intact sexually-experienced animals were mated weekly to determine if regular neural activation enhances cell survival 7 weeks after BrdU in MeP and MPOA. Weekly mating failed to increase cell survival in MeP (8.1±1.6 vs. 9.9 ±3.2 cells/mm 2 ) or MPOA (3.9±0.7 vs. 3.4±0.3 cells/mm 2 ). Furthermore, mating at the time of BrdU injection did not stimulate cell proliferation in MeP (8.9±1.7 vs. 8.1±1.6 cells/mm 2 ) or MPOA (3.6 ±0.5 vs. 3.9±0.7 cells/mm 2 ). Taken together, our results demonstrate a limited capacity for neurogenesis in the mating circuitry. Specifically, cell proliferation in MeP and MPOA are differentially influenced by testosterone, and the birth and survival of new cells in either region are not enhanced by reproductive activity.

Prenatal androgens masculinize postnatal reproductive neuroendocrine function and behavior in sheep. Testosterone treatment of pregnant ewes during midgestation masculinizes sexual behavior and luteinizing hormone secretion in female lambs, presumably in part via aromatization and estrogen receptor (ESR) binding in the brain. We hypothesized that male and female sheep also differ in the number and distribution of ESR-containing neurons. If so, ESR expression should be sensitive to prenatal hormones delivered exogenously or in situ. ESR alpha (ESR1) was compared by immunocytochemistry in male and female lambs at the end of gestation, as well as in fetal females exposed prenatally to testosterone or dihydrotestosterone. ESR1-positive neurons were abundant in the posteromedial bed nucleus of the stria terminalis (BSTpm), medial preoptic area (MPOA), posterior medial amygdaloid nucleus (MeP), amygdalohippocampal area (AHi), ventromedial hypothalamic nuclei (VMH), and arcuate hypothalamic nuclei (ARC). In females, the ARC had the largest number of stained cells (mean 6 SEM, 475.6 6 57.4 cells/0.173 mm 2 ), while staining intensity was greatest in the MPOA (mean 6 SEM gray level, 31.3 6 5.3). The mean 6 SEM integrated gray level (IGL) was high in the ARC (0.63 6 0.13) and in the MPOA (0.51 6 0.08). The mean 6 SEM IGL was low in the MeP (0.31 6 0.10) and in the BSTpm (0.21 6 0.06), while it was intermediate in the AHi (0.36 6 0.10) and in the VMH (0.37 6 0.07). ESR immunostaining was not significantly different in male and female fetal lambs, nor in females fetuses exposed prenatally to androgens (P . 0.05). However, ESR1 staining was significantly increased in the ARC, MPOA, and AHi of adult rams vs. adult ewes. These results suggest that brain ESR immunoreactivity in fetal lambs is unlikely to account for postnatal sex differences in reproductive function. Instead, sex differences in ESR emerge postnatally.

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Although neutrophil recruitment is required for immunity against Staphylococcus aureus, a role for T cells has been suggested based on the increased susceptibility of humans who have altered T cell immune responses to S. aureus cutaneous infections. Here, the contribution of T cells to host defense was investigated in a mouse model of S. aureus cutaneous infection. Mice deficient in γδ but not αβ T cells had substantially larger skin lesions with higher bacterial counts and impaired neutrophil recruitment compared with wild-type mice. This neutrophil recruitment was dependent upon epidermal Vγ5+ γδ T cell production of IL-17 but not IL-21 and IL-22. Further, IL-17 induction required IL-1, TLR2 and IL-23 and was critical for host defense, since IL-17R-deficient mice had a similar phenotype as γδ T cell-deficient mice. Importantly, γδ T cell deficient mice treated with a single dose of recombinant IL-17 had lesion sizes and bacterial counts that resembled wild-type mice, demonstrating that IL-17 can restore the impaired immunity in γδ T cell deficient mice. This study defines a novel role for IL-17-producing epidermal γδ T cells in innate immunity against S. aureus.