Showing papers on "Immune system published in 2012"
TL;DR: The discovery of the immune basis of allograft arteriosclerosis demonstrated that inflammation per se can drive arterial hyperplasia, even in the absence of traditional risk factors.
Abstract: Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis. Unraveling the roles of cytokines as inflammatory messengers provided a mechanism whereby risk factors for atherosclerosis can alter arterial biology, and produce a systemic milieu that favors atherothrombotic events. The discovery of the immune basis of allograft arteriosclerosis demonstrated that inflammation per se can drive arterial hyperplasia, even in the absence of traditional risk factors. Inflammation regulates aspects of plaque biology that trigger the thrombotic complications of atherosclerosis. Translation of these discoveries to humans has enabled both novel mechanistic insights and practical clinical advances.
4,307 citations
TL;DR: In this Opinion article, the context-specific nature of infiltrating immune cells can affect the prognosis of patients is discussed.
Abstract: Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.
3,759 citations
TL;DR: This work considers myeloid cells as an intricately connected, complex, single system and focuses on how tumours manipulate the myeloids system to evade the host immune response.
Abstract: Here, the authors discuss how the immune activities of myeloid cells, such as macrophages and dendritic cells, are affected by the immunosuppressive tumour environment. They propose that tumours can evade the immune system by promoting aberrant differentiation and function of the entire myeloid system.
2,966 citations
TL;DR: It is shown that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and themicroglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3.
2,864 citations
TL;DR: How cell-intrinsic changes in important structural cells can perpetuate the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix–producing myofibroblasts is described.
Abstract: Fibrosis is a key aspect of many chronic inflammatory diseases and can affect almost every tissue in the body. This review discusses recent advances in our understanding of the mechanisms of fibrosis, focusing on the innate and adaptive immune responses. It also describes how some of these crucial pathogenic pathways are being therapeutically targeted in the clinic.
2,492 citations
TL;DR: Cellular and molecular mechanisms in the differentiation and function of regulatory T cells and their role in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation are discussed.
Abstract: The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell–mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.
2,356 citations
TL;DR: Induction of the B7-H1/PD-1 pathway may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity and may explain how melanomas escape immune destruction despite endogenous antitUMor immune responses.
Abstract: In the movie The Great Escape , “problem” prisoners with multiple escape attempts are put in an “escape-proof” POW camp, where they use their cleverness and specialized skills to outwit their captors. However, when it comes to escaping, even Steve McQueen doesn’t have anything on cancer cells. Although human cancers express tumor antigens recognized by the immune system, host immune responses often fail to control tumor growth. Taube et al. now explain one way in which tumor cells may adapt to escape from immune surveillance.
The researchers found a strong association between expression of the immune-inhibitory molecule B7-H1 (PD-L1) on melanocytes and immune cell infiltration into tumors in patients with different stages of melanoma. The B7-H1+ melanocytes were found directly adjacent to the immune cells, with interferon-γ detected at the melanocyte–immune cell interface. Interferon-γ, which is secreted by the immune cells, induces B7-H1 expression; thus, the tumor may adapt by causing immune cells to trigger their own inhibition. Indeed, patients with B7-H1+ metastatic melanoma had prolonged overall survival when compared with B7-H1− metastatic melanoma patients, perhaps suggesting that B7-H1 expression by the tumors is stimulated by a more successful immune response. It remains to be seen whether blocking B7-H1 in these patients will further improve survival. But it is clear that for both prisoners and tumors, adaptation is the key to escape.
1,924 citations
TL;DR: Dendritic cells are an essential target in efforts to generate therapeutic immunity against cancer owing to their ability to control both immune tolerance and immunity.
Abstract: Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.
1,737 citations
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TL;DR: The epidemiology, immunobiology, amd natural history of Crohn's disease is discussed; new treatment goals and risk stratification of patients are described; and an evidence based rational approach to diagnosis is provided.
1,700 citations
TL;DR: Findings supporting the conclusion that IgE and mast cells can have both interdependent and independent roles in the complex immune responses that manifest clinically as asthma and other allergic disorders are discussed.
Abstract: Immunoglobulin E (IgE) antibodies and mast cells have been so convincingly linked to the pathophysiology of anaphylaxis and other acute allergic reactions that it can be difficult to think of them in other contexts. However, a large body of evidence now suggests that both IgE and mast cells are also key drivers of the long-term pathophysiological changes and tissue remodeling associated with chronic allergic inflammation in asthma and other settings. Such potential roles include IgE-dependent regulation of mast-cell functions, actions of IgE that are largely independent of mast cells and roles of mast cells that do not directly involve IgE. In this review, we discuss findings supporting the conclusion that IgE and mast cells can have both interdependent and independent roles in the complex immune responses that manifest clinically as asthma and other allergic disorders.
1,391 citations
TL;DR: This work discusses how various networks underlie the etiology of the inflammatory component of insulin resistance, with a particular focus on the central roles of macrophages in adipose tissue and liver.
Abstract: It is now recognized that obesity is driving the type 2 diabetes epidemic in Western countries Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes and cardiovascular disease, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated Recent advances in deciphering the various cellular and signaling networks that participate in linking the immune and metabolic systems together have contributed to understanding of the pathogenesis of metabolic diseases and may also inform new therapeutic strategies based on immunomodulation Here we discuss how these various networks underlie the etiology of the inflammatory component of insulin resistance, with a particular focus on the central roles of macrophages in adipose tissue and liver
TL;DR: A strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens is defined and it is argued strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.
Abstract: Inhibitory receptors on immune cells are pivotal regulators of immune escape in cancer. Among these inhibitory receptors, CTLA-4 (targeted clinically by ipilimumab) serves as a dominant off-switch while other receptors such as PD-1 and LAG-3 seem to serve more subtle rheostat functions. However, the extent of synergy and cooperative interactions between inhibitory pathways in cancer remain largely unexplored. Here, we reveal extensive coexpression of PD-1 and LAG-3 on tumor-infiltrating CD4(+) and CD8(+) T cells in three distinct transplantable tumors. Dual anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors that were largely resistant to single antibody treatment. Despite minimal immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in multiple organs, leading to eventual lethality. However, Lag3(-/-)Pdcd1(-/-) mice showed markedly increased survival from and clearance of multiple transplantable tumors. Together, these results define a strong synergy between the PD-1 and LAG-3 inhibitory pathways in tolerance to both self and tumor antigens. In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer.
TL;DR: In all malignancies, NF‐κB acts in a cell type‐specific manner: activating survival genes within cancer cells and inflammation‐promoting genes in components of the tumor microenvironment, yet, the complex biological functions of NF-κB have made its therapeutic targeting a challenge.
Abstract: The nuclear factor-κB (NF-κB) transcription factor family has been considered the central mediator of the inflammatory process and a key participant in innate and adaptive immune responses. Coincident with the molecular cloning of NF-κB/RelA and identification of its kinship to the v-Rel oncogene, it was anticipated that NF-κB itself would be involved in cancer development. Oncogenic activating mutations in NF-κB genes are rare and have been identified only in some lymphoid malignancies, while most NF-κB activating mutations in lymphoid malignancies occur in upstream signaling components that feed into NF-κB. NF-κB activation is also prevalent in carcinomas, in which NF-κB activation is mainly driven by inflammatory cytokines within the tumor microenvironment. Importantly, however, in all malignancies, NF-κB acts in a cell type-specific manner: activating survival genes within cancer cells and inflammation-promoting genes in components of the tumor microenvironment. Yet, the complex biological functions of NF-κB have made its therapeutic targeting a challenge.
TL;DR: Targeting the production, degradation, and responsiveness to PGE2 provides tools to modulate the patterns of immunity in a wide range of diseases, from autoimmunity to cancer.
Abstract: PGE(2), an essential homeostatic factor, is also a key mediator of immunopathology in chronic infections and cancer. The impact of PGE(2) reflects the balance between its cyclooxygenase 2-regulated synthesis and 15-hydroxyprostaglandin dehydrogenase-driven degradation and the pattern of expression of PGE(2) receptors. PGE(2) enhances its own production but suppresses acute inflammatory mediators, resulting in its predominance at late/chronic stages of immunity. PGE(2) supports activation of dendritic cells but suppresses their ability to attract naive, memory, and effector T cells. PGE(2) selectively suppresses effector functions of macrophages and neutrophils and the Th1-, CTL-, and NK cell-mediated type 1 immunity, but it promotes Th2, Th17, and regulatory T cell responses. PGE(2) modulates chemokine production, inhibiting the attraction of proinflammatory cells while enhancing local accumulation of regulatory T cells cells and myeloid-derived suppressor cells. Targeting the production, degradation, and responsiveness to PGE(2) provides tools to modulate the patterns of immunity in a wide range of diseases, from autoimmunity to cancer.
TL;DR: All human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination, showing that CD47 is a commonly expressed molecule on all cancers, its function to blockphagocytosis is known, and blockade of its function leads to tumor cell phagcytosis and elimination.
Abstract: CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination CD47 is therefore a validated target for cancer therapies
TL;DR: Encouraging early clinical results using blocking agents against components of the PD-1 pathway have validated its importance as a target for cancer immunotherapy.
TL;DR: It is shown that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens.
Abstract: Adaptive features of innate immunity, recently described as “trained immunity,” have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guerin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte–independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.
TL;DR: It is shown that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance, and data suggest that MAIT cells use these metabolites to detect microbial infection.
Abstract: Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection.
TL;DR: It is demonstrated that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and shown that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.
Abstract: Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective antitumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2(-/-) mice that phenotypically resemble nascent primary tumour cells. Using class I prediction algorithms, we identify mutant spectrin-β2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T-cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-β2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.
TL;DR: Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.
Abstract: The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.
TL;DR: The factors that are important for Breg differentiation and for their effector function in both mouse and human are discussed.
Abstract: B cells are regarded for their capacity to produce antibody. However, recent advances in B cell biology have capitalized on old findings and demonstrated that B cells also release a broad variety of cytokines. As with T helper cells, B cells can be classified into subsets according to the cytokine milieu that they produce. One functional B cell subset, regulatory B cells (Bregs), has recently been shown to contribute to the maintenance of the fine equilibrium required for tolerance. Bregs restrain the excessive inflammatory responses that occur during autoimmune diseases or that can be caused by unresolved infections. Pivotal to Breg function is interleukin-10 (IL-10), which inhibits proinflammatory cytokines and supports regulatory T cell differentiation. This review reports and discusses the factors that are important for Breg differentiation and for their effector function in both mouse and human.
TL;DR: Recently, fish-derived omega-3 fatty acids EPA and DHA have been associated with fetal development, cardiovascular function, and Alzheimer's disease as discussed by the authors, which has been linked to promising results in prevention, weight management, and cognitive function in those with very mild Alzheimer’s disease.
TL;DR: In this paper, the authors colonized GF mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota.
TL;DR: Recent developments point towards a multilayered plant innate immune system comprised of self-surveillance, systemic signalling and chromosomal changes that together establish effective immunity.
Abstract: Vertebrates have evolved a sophisticated adaptive immune system that relies on an almost infinite diversity of antigen receptors that are clonally expressed by specialized immune cells that roam the circulatory system. These immune cells provide vertebrates with extraordinary antigen-specific immune capacity and memory, while minimizing self-reactivity. Plants, however, lack specialized mobile immune cells. Instead, every plant cell is thought to be capable of launching an effective immune response. So how do plants achieve specific, self-tolerant immunity and establish immune memory? Recent developments point towards a multilayered plant innate immune system comprised of self-surveillance, systemic signalling and chromosomal changes that together establish effective immunity.
TL;DR: M modes of regulation of IL-10 gene expression in immune effector cell types are discussed, including signal transduction, epigenetics, promoter architecture, and post-transcriptional regulation, and how aberrant regulation contributes to immunopathology and disease progression.
Abstract: Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that plays a central role in limiting host immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis Dysregulation of IL-10 is associated with enhanced immunopathology in response to infection as well as increased risk for development of many autoimmune diseases Thus a fundamental understanding of IL-10 gene expression is critical for our comprehension of disease progression and resolution of host inflammatory response In this review, we discuss modes of regulation of IL-10 gene expression in immune effector cell types, including signal transduction, epigenetics, promoter architecture, and post-transcriptional regulation, and how aberrant regulation contributes to immunopathology and disease progression
TL;DR: The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of "trained immunity" and may be employed for the design of improved vaccination strategies.
TL;DR: It is shown that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1, which substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.
Abstract: The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease. Here, we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility to chemically induced colitis, which was the result of altered responses to indigenous fungi. In humans, we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together, our findings reveal a eukaryotic fungal community in the gut (the "mycobiome") that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.
TL;DR: The production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed.
Abstract: Interferon-α (IFNα) and IFNβ, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases.
TL;DR: M1/M2 demonstrated the importance of Innate Immunity and how it is linked to Adaptive Immunity in a beautifully counterbalanced system and recommended that Immune Type 1 or 2 (IT1, IT2) would be a simpler and unifying terminology going forward.
Abstract: The purpose of immunology is simple. Cure or prevent disease. M1/M2 is useful because it is simple. M1/M2 describes the two major and opposing activities of macrophages. M1 activity inhibits cell proliferation and causes tissue damage while M2 activity promotes cell proliferation and tissue repair. Remarkably, the molecules primarily responsible for these "Fight" (NO) or "Fix" (Ornithine) activities both arise from arginine, and via enzymatic pathways (iNOS and arginase) that down regulate each other. The names M1 and M2 were chosen because M1 and M2 macrophages promote Th1 and Th2 responses, respectively. Products of Th1 and Th2 responses (e.g., IFN-γ, IL-4) also down regulate M2 and M1activity, respectively. Thus, M1/M2 demonstrated the importance of Innate Immunity and how it is linked to Adaptive Immunity in a beautifully counterbalanced system. "Civilization" and increased longevity present new disease challenges such as cancer and atherosclerosis that do not display classical "foreign" antigens. And, these diseases are often associated with (or caused by) M1- or M2- type responses that were formerly useful for fighting infections, but now are inappropriate in our increasingly "germ-free" societies. In turn, there is considerable potential for modulating M1 or M2 Innate responses in modern diseases to achieve better health. Finally, since M1 and Th1 (or M2 and Th2) often work in concert to produce characteristic immune responses and disease pathologies, it is recommended that Immune Type 1 or 2 (IT1, IT2) would be a simpler and unifying terminology going forward.
TL;DR: In this paper, the skin microbiota has an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function, and skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor.
Abstract: Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease.