SUMMARY Long recognized to be potent suppressors of immune responses, Foxp3+CD4+ regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloidlineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies.

Summary Foxp3+ T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. Here we identified Foxp3+ T cells expressing the co-inhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses pro-inflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT+ Treg cells as an activated Treg subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cell cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.

Within the human gut reside diverse microbes coexisting with the host in a mutually advantageous relationship. Evidence has revealed the pivotal role of the gut microbiota in shaping the immune system. To date, only a few of these microbes have been shown to modulate specific immune parameters. Herein, we broadly identify the immunomodulatory effects of phylogenetically diverse human gut microbes. We monocolonized mice with each of 53 individual bacterial species and systematically analyzed host immunologic adaptation to colonization. Most microbes exerted several specialized, complementary, and redundant transcriptional and immunomodulatory effects. Surprisingly, these were independent of microbial phylogeny. Microbial diversity in the gut ensures robustness of the microbiota's ability to generate a consistent immunomodulatory impact, serving as a highly important epigenetic system. This study provides a foundation for investigation of gut microbiota-host mutualism, highlighting key players that could identify important therapeutics.

Maternal immune activation (MIA) contributes to behavioral abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring1-4. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing Autism Spectrum Disorder (ASD)5-7. We recently demonstrated that interleukin-17a (IL-17a) produced by Th17 cells, CD4+ T helper effector cells involved in multiple inflammatory conditions, is required in pregnant mice to induce behavioral as well as cortical abnormalities in the offspring exposed to MIA8. However, it is unclear if other maternal factors are required to promote MIA-associated phenotypes. Moreover, underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here, we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote Th17 cell differentiation. Pregnant mice that had been colonized with the mouse commensal segmented filamentous bacteria (SFB) or human commensal bacteria that induce intestinal Th17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells (DCs) from pregnant, but not from non-pregnant, females upon exposure to MIA secrete IL-1β/IL-23/IL-6 and stimulate T cells to produce IL-17a. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce Th17 cells may increase the risk for neurodevelopmental disorders in offspring of pregnant mothers undergoing immune system activation due to infections or autoinflammatory syndromes.

Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8 + T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients. IntroductionMetastatic disease is the major cause of death by cancer (1, 2). Metastasis is a complex multistage process that requires cancer cells within the primary tumor to invade the local tissue and enter the blood or lymphatic vessels. Tumor cells need to survive in the circulation and migrate across vessel walls in order to colonize new sites and grow to form secondary tumors (3). The traditional view has been that tumor cell dissemination occurs late in cancer development (4-6); however, this notion has recently been challenged. Several expression profiling studies (7-10) suggest that the propensity of cancer cells to metastasize is acquired relatively early during tumor progression (reviewed in ref. 11). In addition, examination of bone marrow from early stage cancer patients without overt metastases (reviewed in refs. 12 and 13) and tumorbearing mice (14) revealed that disseminated tumor cells (DTCs) are present at much earlier time points than expected. We now need to understand the significance of these DTCs. Specifically, we must determine how early DTCs contribute to clinically relevant macrometastases and identify the mechanisms involved in the development, maintenance, and breakdown of dormancy.Transplanted tumor models in rodents are often used to study metastasis, with most of our current knowledge of cancer cell dissemination being drawn from xenograft models. However, these models often fail to recapitulate the gradual process of tumorigenesis that is observed in humans, and, in the case of immuno-