The skin is a site of constant dialog between the immune system and commensal bacteria. However, the molecular mechanisms that allow us to tolerate the presence of skin commensals without eliciting ...destructive inflammation are unknown. Using a model system to study the antigen-specific response to S. epidermidis, we demonstrated that skin colonization during a defined period of neonatal life was required for establishing immune tolerance to commensal microbes. This crucial window was characterized by an abrupt influx of highly activated regulatory T (Treg) cells into neonatal skin. Selective inhibition of this Treg cell wave completely abrogated tolerance. Thus, the host-commensal relationship in the skin relied on a unique Treg cell population that mediated tolerance to bacterial antigens during a defined developmental window. This suggests that the cutaneous microbiome composition in neonatal life is crucial in shaping adaptive immune responses to commensals, and disrupting these interactions might have enduring health implications.
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•Skin bacteria activate antigen-specific T cells across an intact skin barrier•Tolerance to skin commensal bacteria is preferentially established in neonatal life•A unique wave of activated regulatory T cells enters skin in this critical window•Blocking entry of Treg cells into neonatal skin prevents tolerance to commensals
The mechanisms promoting immune tolerance to skin commensal bacteria are unknown. Using a model system to assay commensal-specific T cell responses, Rosenblum and colleagues demonstrate that an abrupt accumulation of regulatory T cells in neonatal skin mediates tolerance to skin commensal bacteria during this crucial developmental window.
Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to ...specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options.
We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype.
Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs.
Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition.
This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.
Foxp3-expressing regulatory T cells (Tregs) reside in tissues where they control inflammation and mediate tissue-specific functions. The skin of mice and humans contain a large number of Tregs; ...however, the mechanisms of how these cells function in skin remain largely unknown. In this article, we show that Tregs facilitate cutaneous wound healing. Highly activated Tregs accumulated in skin early after wounding, and specific ablation of these cells resulted in delayed wound re-epithelialization and kinetics of wound closure. Tregs in wounded skin attenuated IFN-γ production and proinflammatory macrophage accumulation. Upon wounding, Tregs induce expression of the epidermal growth factor receptor (EGFR). Lineage-specific deletion of EGFR in Tregs resulted in reduced Treg accumulation and activation in wounded skin, delayed wound closure, and increased proinflammatory macrophage accumulation. Taken together, our results reveal a novel role for Tregs in facilitating skin wound repair and suggest that they use the EGFR pathway to mediate these effects.
The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells ...influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of Tregs and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.
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•Treg activation in skin closely correlates with the HF cycle•Tregs localize to HFSCs and play a major role in HF regeneration•Tregs facilitate HFSC proliferation and differentiation to initiate HF cycling•Treg expression of Jagged 1 is required for efficient hair regeneration
Localized regulatory T cells (Tregs) regulate the hair follicle cycle by driving Notch-dependent stem cell proliferation and differentiation.
Regulatory T cells (Tregs) are required to establish immune tolerance to commensal microbes. Tregs accumulate abruptly in the skin during a defined window of postnatal tissue development. However, ...the mechanisms mediating Treg migration to neonatal skin are unknown. Here we show that hair follicle (HF) development facilitates the accumulation of Tregs in neonatal skin and that upon skin entry these cells localize to HFs, a primary reservoir for skin commensals. Further, germ-free neonates had reduced skin Tregs indicating that commensal microbes augment Treg accumulation. We identified Ccl20 as a HF-derived, microbiota-dependent chemokine and found its receptor, Ccr6, to be preferentially expressed by Tregs in neonatal skin. The Ccl20-Ccr6 pathway mediated Treg migration in vitro and in vivo. Thus, HF morphogenesis, commensal microbe colonization, and local chemokine production work in concert to recruit Tregs into neonatal skin, thereby establishing this tissue Treg niche early in life.
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•Hair follicle development facilitates Treg accumulation in neonatal skin•Commensal microbes augment Treg accumulation in neonatal skin and induce Ccl20 expression•The Ccl20-specific receptor, Ccr6, is preferentially expressed by neonatal skin Tregs•The Ccl20-Ccr6 pathway mediates neonatal Treg migration and skin-homing
Regulatory T cells (Tregs) accumulate in the skin during a defined window of postnatal development, but the underlying mechanisms are unclear. Scharschmidt et al. demonstrate that microbial colonization of developing hair follicles is required for Treg migration and homing into neonatal skin and is mediated by the Ccl20-Ccr6 pathway.
Objective
Adoptive Treg cell therapy has great potential to treat autoimmune disease. Currently, very little is known about how these cells impact inflamed tissues. This study was undertaken to ...elucidate how autologous Treg cell therapy influences tissue inflammation in human autoimmune disease.
Methods
We describe a systemic lupus erythematosus (SLE) patient with active skin disease who received adoptive Treg therapy. We comprehensively quantified Treg cells and immune activation in peripheral blood and skin, with data obtained at multiple time points posttreatment.
Results
Deuterium tracking of infused Treg cells revealed the transient presence of cells in peripheral blood, accompanied by increased percentages of highly activated Treg cells in diseased skin. Flow cytometric analysis and whole transcriptome RNA sequencing revealed that Treg cell accumulation in skin was associated with a marked attenuation of the interferon‐γ pathway and a reciprocal augmentation of the interleukin‐17 (IL‐17) pathway. This phenomenon was more pronounced in skin relative to peripheral blood. To validate these findings, we investigated Treg cell adoptive transfer of skin inflammation in a murine model and found that it also resulted in a pronounced skewing away from Th1 immunity and toward IL‐17 production.
Conclusion
We report the first case of a patient with SLE treated with autologous adoptive Treg cell therapy. Taken together, our results suggest that this treatment leads to increased activated Treg cells in inflamed skin, with a dynamic shift from Th1 to Th17 responses.
The actions of the immune system are finely tuned, involving complex communication and coordination between diverse immune and non-immune cells across the tissues of the body. A healthy immune system ...requires a precise balance between immunity and tolerance. Regulatory T cells (Tregs) have long been appreciated as one of the master regulators of this balance; their importance is underscored by the autoimmunity that develops in mice and humans when Tregs are missing or dysfunctional. In addition to the immunoregulatory roles of Tregs in suppressing autoimmunity and inflammation via control of adaptive and innate immune responses, several non-immune modulatory functions of Tregs have been identified in recent years. In this review, we have highlighted the growing literature on the action of Tregs in metabolism, stem cell maintenance, tissue repair, and angiogenesis. Alongside Tregs' immune suppressive role, these non-suppressive activities comprise a key function of Tregs in regulating health and disease. As Tregs receive increasing attention as therapeutic targets, understanding their non-canonical functions may become an important feature of Treg-directed interventions.
Memory regulatory T cells reside in human skin Sanchez Rodriguez, Robert; Pauli, Mariela L; Neuhaus, Isaac M ...
The Journal of clinical investigation,
03/2014, Volume:
124, Issue:
3
Journal Article
Peer reviewed
Open access
Regulatory T cells (Tregs), which are characterized by expression of the transcription factor Foxp3, are a dynamic and heterogeneous population of cells that control immune responses and prevent ...autoimmunity. We recently identified a subset of Tregs in murine skin with properties typical of memory cells and defined this population as memory Tregs (mTregs). Due to the importance of these cells in regulating tissue inflammation in mice, we analyzed this cell population in humans and found that almost all Tregs in normal skin had an activated memory phenotype. Compared with mTregs in peripheral blood, cutaneous mTregs had unique cell surface marker expression and cytokine production. In normal human skin, mTregs preferentially localized to hair follicles and were more abundant in skin with high hair density. Sequence comparison of TCRs from conventional memory T helper cells and mTregs isolated from skin revealed little homology between the two cell populations, suggesting that they recognize different antigens. Under steady-state conditions, mTregs were nonmigratory and relatively unresponsive; however, in inflamed skin from psoriasis patients, mTregs expanded, were highly proliferative, and produced low levels of IL-17. Taken together, these results identify a subset of Tregs that stably resides in human skin and suggest that these cells are qualitatively defective in inflammatory skin disease.
Background Evidence from adult psoriasis studies implicates an imbalance between regulatory and effector T cells, particularly TH -17–producing T cells, in the pathogenesis of psoriasis. Little is ...known about the immunopathology of psoriasis in children. Objective We sought to functionally characterize the inflammatory cell profiles of psoriatic plaques from pediatric patients and compare them with healthy, age-matched controls and adult psoriasis patients. Methods Skin samples from pediatric psoriasis patients and healthy controls were analyzed by multiparameter flow cytometry to determine the dominant immune cell subsets present and cytokines produced. Results Lesional tissue from pediatric psoriasis patients had significantly increased interleukin (IL) 22 derived from CD4+ and CD8+ cells compared with the tissues from healthy pediatric controls and adult psoriasis patients. Tissue from pediatric psoriasis patients had significantly less elevation of IL-17 derived from CD4+ and CD8+ cells compared with the tissue from adult psoriasis patients. In contrast with the lesions from adult patients, lesional skin in pediatric patients with psoriasis did not have increases in regulatory T cells. Limitations This is a pilot study, thus the sample size is small. Conclusion Significant differences in IL-17 and IL-22 expression were observed in the pediatric psoriasis patients compared with pediatric healthy controls and adult psoriasis patients. IL-22 might be relevant in the pathogenesis of pediatric psoriasis and represents a potential treatment target unique to pediatric psoriasis.
Background Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by sterile abscesses and fistulae predominantly affecting the axillae and groin. Various biologic agents have ...been attempted for HS, but there is still no definitive treatment. Objectives We sought to evaluate the efficacy, safety, and tolerability of anakinra in the treatment of moderate to severe HS. Methods Six patients with moderate to severe HS were enrolled in an open-label study with all patients receiving active treatment for 8 weeks with an additional 8 weeks of follow-up off therapy. Results The 5 patients who completed the 8-week therapy showed a significant mean decrease in their modified Sartorius score of 34.8 points. The physician and patient global assessment of overall activity showed significant reductions between baseline and 8 weeks of therapy: 45.8 points and 35.6 points, respectively. The Dermatology Life Quality Index showed a significant reduction after 8 weeks of treatment with anakinra. Functional T-cell analysis revealed that patients had increased percentages of CD3+ T cells in lesional skin compared with nonlesional skin before therapy. Limitations The limited number of patients and lack of control group are limitations. Conclusions Anakinra demonstrated decreased HS disease activity by both objective and subjective measures.
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