The microbiome can promote or disrupt human health by influencing both adaptive and innate immune functions. We tested whether bacteria that normally reside on human skin participate in host defense by killing Staphylococcus aureus, a pathogen commonly found in patients with atopic dermatitis (AD) and an important factor that exacerbates this disease. High-throughput screening for antimicrobial activity against S.aureus was performed on isolates of coagulase-negative Staphylococcus (CoNS) collected from the skin of healthy and AD subjects. CoNS strains with antimicrobial activity were common on the normal population but rare on AD subjects. A low frequency of strains with antimicrobial activity correlated with colonization by S.aureus. The antimicrobial activity was identified as previously unknown antimicrobial peptides (AMPs) produced by CoNS species including Staphylococcus epidermidis and Staphylococcus hominis. These AMPs were strain-specific, highly potent, selectively killed S.aureus, and synergized with the human AMP LL-37. Application of these CoNS strains to mice confirmed their defense function in vivo relative to application of nonactive strains. Strikingly, reintroduction of antimicrobial CoNS strains to human subjects with AD decreased colonization by S.aureus. These findings show how commensal skin bacteria protect against pathogens and demonstrate how dysbiosis of the skin microbiome can lead to disease.

Immune regulatory CD4 ؉ CD25 ؉ cells play a vital role in the induction and maintenance of self-tolerance and the prevention of autoimmunity. Recently, CD4 ؉ CD25 ؉ cells have been shown to be required for the ex vivo induction of tolerance to alloantigen via costimulatory blockade and to inhibit allogeneic skin graft rejection. Data presented here demonstrate that CD4 ؉ CD25 ؉ cells play an important role in graft-versus-host disease (GVHD) generation. Depletion of CD4 ؉ CD25 ؉ cells from the donor T-cell inoculum or in vivo CD25-depletion of the recipient before transplantation resulted in increased GVHD mediated by CD4 ؉ or whole T cells in several strain combinations irrespective of the total body irradiation conditioning regime. The infusion of freshly purified donor CD4 ؉ CD25 ؉ cells modestly inhibited GVHD when administered in equal numbers with whole CD4 ؉ cells. Because CD4 ؉ CD25 ؉ cells only account for 5% to 10% of the total CD4 ؉ population, the administration of high numbers of fresh donor CD4 ؉ CD25 ؉ cells may not be clinically practical. However, we found that large numbers of CD4 ؉ CD25 ؉ cells can be obtained by ex vivo activation and expansion. Cultured CD4 ؉ CD25 ؉ cells, administered in equal numbers with CD4 ؉ T cells or CD25-depleted whole T cells, resulted in significant inhibition of rapidly lethal GVHD. To our knowledge, this study is the first to demonstrate that activated, cultured CD4 ؉ CD25 ؉ cells can offer substantial protection in a relevant in vivo animal model of disease. IntroductionImmune regulatory CD4 ϩ CD25 ϩ cells are essential for the induction and maintenance of self-tolerance and for the prevention of autoimmunity. These thymically derived professional regulatory cells prevent the activation and proliferation of autoreactive T cells that have escaped thymic deletion or recognize extrathymic antigens. Elegant studies by several investigators have elucidated their vital role in T-cell homeostasis and immune regulation. [1][2][3][4][5][6][7][8][9] Sakaguchi et al 1 found that the transfer of CD4 ϩ CD25 Ϫ T cells into nude mice led to the development of autoimmune disorders that could be prevented by the cotransfer of CD4 ϩ CD25 ϩ T cells. Suri-Payer et al 3 found that susceptible mouse strains made CD4 ϩ CD25 ϩ deficient by neonatal thymectomy developed a wide spectrum of organ-specific autoimmunities that could be prevented by the transfer of CD4 ϩ CD25 ϩ T cells by 10 to 14 days of age. They also found that CD4 ϩ CD25 ϩ T cells could inhibit autoimmunity induced by autoantigen-specific T-cell clones. 3 Data also indicate that the role of CD4 ϩ CD25 ϩ cells is not limited to self-tolerance and the prevention of autoimmunity. Studies indicate that depletion of these regulatory cells led to increased tumorspecific immune responses and eradication of tumors in otherwise nonresponding animals. 10,11 Fewer studies have addressed the role of CD4 ϩ CD25 ϩ T cells in alloresponses or in transplantation. Sakaguchi et al 1 found that nude mice rejected allogeneic skin grafts fa...

Myeloid-derived suppressor cells (MDSCs

Immune regulatory CD4+CD25+ cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4+CD25+ cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4+ T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte–associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo. CD4+CD25+ T cells were found to be potent regulators of alloresponses. Depletion of CD4+CD25+ T cells from the CD4+ responder population completely abrogated ex vivo tolerance induction to alloantigen as measured by intact responses to alloantigen restimulation in vitro and in vivo. Addback of CD4+CD25+ T cells to CD4+CD25− cultures restored tolerance induction. These data are the first to indicate that CD4+CD25+ cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

Graft-versus-host disease (GVHD) is