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Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases. Editor's Summary: Programmed cell death-1 (PD-1) is well known as an immune checkpoint receptor on T cells that can inhibit activation upon engagement with its ligands PD-L1 or PD-L2. PD-1 has largely been considered to function as a monomer, but Philips et al. now show that PD-1 can form dimers in cis via transmembrane domain interactions. They observed that limiting PD-1 dimerization weakens T cell inhibition upon ligand engagement, which enhances antitumor and cytotoxic T cell function and promotes autoimmunity. These findings may shape ongoing efforts to more effectively block PD-1 function or, conversely, to develop PD-1 agonists. —Christiana Fogg [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) and macrophages are critical to innate and adaptive immunity to the intestinal bacterial microbiota. Here, we identify a myeloid-derived mucosal DC in mice, which populates the entire lamina propria of the small intestine. Lamina propria DCs were found to depend on the chemokine receptor C[X.sub.3]CR1 to form transepithelial dendrites, which enable the cells to directly sample luminal antigens. C[X.sub.3]CR1 was also found to control the clearance of entero-invasive pathogens by DCs. Thus, C[X.sub.3]CR1-dependent processes, which control host interactions of specialized DCs with commensal and pathogenic bacteria, may regulate immunological tolerance and inflammation., Antigen-presenting dendritic cells (DCs) play a crucial role in establishing immunity to pathogens, tolerance to self-antigens, and the induction of organ-specific autoimmunity (1-5). Through their interactions with antigen-specific T lymphocytes, [...]

Intestinal intraepithelial T lymphocytes (IELs) are likely to play a key role in host mucosal immunity and, unlike other T cells, have been proposed to differentiate from local precursors rather than from thymocytes. We show here that IELs expressing the αβ T cell receptor are derived from precursors that express RORγt, an orphan nuclear hormone receptor detected only in immature [CD4].sup.+][CD8.sup.+] thymocytes, fetal lymphoid tissue--inducer (LTi) cells, and LTi-like cells in cryptopatches within the adult intestinal lamina propria. Using cell fate mapping, we found that all intestinal αβ T cells are progeny of [CD4.sup.+][CD8.sup.+] thymocytes, indicating that the adult intestine is not a significant site for αβ T cell development. Our results suggest that intestinal RORγ[t.sup.+] cells are local organizers of mucosal lymphoid tissue., The gut-associated immune system includes mesenteric lymph nodes (mLNs), Peyer's patches (PPs), and T lymphocytes that reside in the intestinal lamina propria (LPLs) and within the single layer of intestinal [...]

Memory T cells are long-lived antigen-experienced T cells that are generally accepted to be direct descendants of proliferating primary effector cells. However, the factors that permit selective survival of these T cells are not well established. We show that homodimeric α chains of the CD8 molecule (CD8αα) are transiently induced on a selected subset of CD8α[β.sup.+] T cells upon antigenic stimulation. These CD8αα molecules promote the survival and differentiation of activated lymphocytes into memory CD8 T cells. Thus, memory precursors can be identified among primary effector cells and are selected for survival and differentiation by CD8αα., The majority of T cells responding during a primary immune response subsequently undergo programmed cell death. However, a fraction of activated T cells survive and differentiate into long-lived memory T [...]

To complete their maturation, most immature thymocytes depend on the simultaneous engagement of their antigen receptor αβ T cell receptor (TCR) and their CD4 or CD8 coreceptors with major histocompatibility complex class II or I ligands, respectively. However, a normal subset of mature αβ[TCR.sup.+] thymocytes did not follow these rules. These thymocytes expressed NK1.1 and a restricted set of αβ TCRs that are intrinsically class I-reactive because their positive selection was class I-dependent but CD8-independent. These cells were [CD4.sup.+] and [CD4.sup.-8.sup.-] but never [CD8.sup.+], because the presence of C caused negative selection. Thus, neither CD4 nor CD8 contributes signals that direct their maturation into the [CD4.sup.+] and [CD4.sup.-8.sup.-]lineages., During the positive selection of [CD4.sup.+8+] double-positive precursor thymocytes, cells bearing major histocompatibility complex (MHC) class I-specific αβ TCRs are recruited into the CD8 lineage, whereas cells bearing class II-specific [...]

Expression of either the CD4 or CD8 glycoproteins discriminates two functionally distinct lineages of T lymphocytes. A null mutation in the gene encoding CD4 impairs the development of the helper cell lineage that is normally defined by CD4 expression. Infection of CD4-null mice with Leishmania has revealed a population of functional helper T celis that develops despite the absence of CD4. These [CD8.sup.-] [alpha beta]T cell [receptor.sup.+] T cells are major histocompatibility complex class II-restricted and produce interferon-γ when challenged with parasite antigens. These results indicate that T lymphocyte lineage commitment and peripheral function need not depend on the function of CD4., The critical role of T cells in the control of murine Leishmania major infection is underscored by the failure of the immune system of T cell-deficient nude or severe combined [...]

keyimage.jpg Maf, macrophages, and metabolic syndrome: Macrophage populations in white adipose tissue (WAT) are thought to play a pivotal role in the development of metabolic syndrome associated with obesity. Vascular-associated adipose macrophages (VAMs) are the predominant macrophage population in WAT, but little is known about their function. Moura Silva et al. identified a population of VAMs dependent on the transcription factor c-MAF in the brain, intestine, and WAT of mice. Using multiple Cre drivers to delete c-MAF in macrophages, the authors define c-MAF as a central transcription factor that regulates the phenotype of VAMs. Loss of c-MAF in VAMs caused increased vascularization in WAT and was protective against obesity and metabolic syndrome. These findings suggest that c-MAF–expressing VAMs in WAT play an important role in regulation of metabolic syndrome. Macrophages are an essential part of tissue development and physiology. Perivascular macrophages have been described in tissues and appear to play a role in development and disease processes, although it remains unclear what the key features of these cells are. Here, we identify a subpopulation of perivascular macrophages in several organs, characterized by their dependence on the transcription factor c-MAF and displaying nonconventional macrophage markers including LYVE1, folate receptor 2, and CD38. Conditional deletion of c-MAF in macrophage lineages caused ablation of perivascular macrophages in the brain and altered muscularis macrophages program in the intestine. In the white adipose tissue (WAT), c-MAF–deficient perivascular macrophages displayed an altered gene expression profile, which was linked to an increased vascular branching. Upon feeding high-fat diet (HFD), mice with c-MAF–deficient macrophages showed improved metabolic parameters compared with wild-type mice, including less weight gain, greater glucose tolerance, and reduced inflammatory cell profile in WAT. These results define c-MAF as a central regulator of the perivascular macrophage transcriptional program in vivo and reveal an important role for this tissue-resident macrophage population in the regulation of metabolic syndrome. [ABSTRACT FROM AUTHOR]

An arthritogenic strain of Subdoligranulum in the gut elicits a local immune response, a precursor to systemic autoimmunity (Chriswell et al.). [ABSTRACT FROM AUTHOR]

Most developing thymocytes undergo apoptosis because they cannot interact productively with molecules encoded by the major histocompatibility complex. Here, we show that mice lacking the orphan nuclear hormone receptor ROR[Gamma] lose thymic expression of the anti-apoptotic factor Bcl-xL. ROR[Gamma] thus regulates the survival of [CD4.sup.+] [8.sup.+] thymocytes and may control the temporal window during which thymocytes can undergo positive selection. ROR[Gamma] was also required for development of lymph nodes and Peyer's patches, but not splenic follicles. In its absence, there was loss of a population of [CD3.sup.-][CD4.sup.+][CD45.sup.+] cells that normally express ROR[Gamma] and that are likely early progenitors of lymphoid organs. Hence, ROR[Gamma] has critical functions in T cell repertoire selection and lymphoid organogenesis., During selection of a T cell repertoire within the thymus, [CD4.sup.+] [CD8.sup.+] (double positive, DP) thymocytes with T cell antigen receptors (TCRs) that recognize complexes of host major histocompatibility complex [...]

Molecular Diversity of the Human T-Gamma Constant Region Genes MOST T LYMPHOCYTES EXPRESS AN antigen-receptor complex consisting of polymorphic and T cell receptor (TCR) subunits in association with several nonpolymorphic [...]

T cell receptor (TCR) signaling requires activation of Zap-70 and Src family tyrosine kinases, but requirements for other tyrosine kinases are less clear. Combined deletion in mice of two Tec kinases, Rlk and Itk, caused marked defects in TCR responses including proliferation, cytokine production, and apoptosis in vitro and adaptive immune responses to Toxoplasma gondii in vivo. Molecular events immediately downstream from the TCR were intact in [rlk.sup.-/-][itk.sup.-/-] cells, but intermediate events including inositol trisphosphate production, calcium mobilization, and mitogen-activated protein kinase activation were impaired, establishing Tec kinases as critical regulators of TCR signaling required for phospholipase C-[Gamma] activation., Stimulation of T lymphocytes through the TCR elicits broad responses required for proper immune function, including cell proliferation, cytokine production, and apoptosis. Key components of TCR signaling are nonreceptor tyrosine [...]

Current recombinant human immunodeficiency virus (HIV) gp120 protein vaccine candidates are unable to elicit antibodies capable of neutralizing infectivity of primary isolates from patients. Here, 'fusion-competent' HIV vaccine immunogens were generated that capture the transient envelope-CD4-coreceptor structures that arise during HIV binding and fusion. In a transgenic mouse immunization model, these formaldehyde-fixed whole-cell vaccines elicited antibodies capable of neutralizing infectivity of 23 of 24 primary HIV isolates from diverse geographic locations and genetic clades A to E. Development of these fusion-dependent immunogens may read to a broadly effective HIV vaccine., The expanding epidemic of HIV infection threatens to engulf more than 40 million persons worldwide by the year 2000 (1). The need for an effective HIV vaccine is urgent, but [...]

The article presents the discussion on better insights into the association of alterated immune responses with metabolic disorders such as obesity and malabsorption syndromes. Topics include promoting local adaptation for increasing abundance of sugars in the diet; and increase in sugar content promoting changes in intestinal transcriptional programs being associated with sugar metabolism.

The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity. Here, we review advances in our understanding of the interactions between resident microbes and the immune system and the implications of these findings for human health. [ABSTRACT FROM AUTHOR]

Intestinal intraepithelial T lymphocytes (IEU) are likely to play a key role in host mucosal immunity and, unlike other T cells, have been proposed to differentiate from local precursors rather than from thymocytes. We show here that IELs expressing the αβ T cell receptor are derived from precursors that express RORγt, an orphan nuclear hormone receptor detected only in immature CD4[sup +]CD8[sup +] thymocytes, fetal lymphoid tissue-inducer (LTi) cells, and LTi-like cells in cryptopatches within the adult intestinal lamina propria. Using cell fate mapping, we found that all intestinal αβ T cells are progeny of CD4[sup +]CD8[sup +] thymocytes, indicating that the adult intestine is not a significant site for αβ T cell development. Our results suggest that intestinal RORγt[sup +] cells are local organizers of mucosal lymphoid tissue. [ABSTRACT FROM AUTHOR]

Presents a response by Gérard Eberl and Dan R. Littman to a letter to the editor about their article on the thymic origin of intestinal αβ T cells.

Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor-related orphan nuclear receptor gamma t (RORgt)-dependent effector T lymphocytes [for example, T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes. [ABSTRACT FROM AUTHOR]

Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα3) produced by RORγt+ innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β(LTα1β2) produced by RORγt+ ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTa in RORgt+ cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition. [ABSTRACT FROM AUTHOR]

Lymphocyte homing, which contributes to inflammation, has been studied extensively in the small intestine, but there is little known about homing to the large intestine, the site most commonly affected in inflammatory bowel disease. GPR15, an orphan heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, controlled the specific homing of T cells, particularly FOXP3+ regulatory T cells (Tregs), to the large intestine lamina propria (LILP). GPR15 expression was modulated by gut microbiota and transforming growth factor-β1, but not by retinoic acid. GPR15-deficient mice were prone to develop more severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient Tregs. Our findings thus describe a T cell-homing receptor for LILP and indicate that GPR15 plays a role in mucosal immune tolerance largely by regulating the influx of Tregs. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 4 (IRF4) and IRF8 regulate B, T, macrophage, and dendritic cell differentiation. They are recruited to cis-regulatory Ets-IRF composite elements by PU.1 or Spi-B. How these IRFs target genes in most I cells is enigmatic given the absence of specific Ets partners. Chromatin immunoprecipitation sequencing in T helper 17 (TH17) cells reveals that IRF4 targets sequences enriched for activating protein 1 (AP-1)-IRF composite elements (AICEs) that are co-bound by BATF, an AP-1 factor required for TH17, B, and dendritic cell differentiation. IRF4 and BATF bind cooperatively to structurally divergent AICEs to promote gene activation and TH17 differentiation. The AICE motif directs assembly of IRF4 or IRF8 with BATF heterodimers and is also used in TH2. B, and dendritic cells. This genomic regulatory element and cognate factors appear to have evolved to integrate diverse immunomodulatory signals. [ABSTRACT FROM AUTHOR]

Memory T cells are long-lived antigen-experienced T cells that are generally accepted to be direct descendants of proliferating primary effector cells. However, the factors that permit selective survival of these T cells are not well established. We show that homodimeric a chains of the CDS molecule (CD8αα) are transiently induced on a selected subset of CD8aβ∼ T cells upon antigenic stimulation. These CD8αα molecules promote the survival and differentiation of activated lymphocytes into memory CD8 T cells. Thus, j memory precursors can be identified among primary effector cells and are , selected for survival and differentiation by CD8αα. [ABSTRACT FROM AUTHOR]

Focuses on a study which showed that mice lacking the orphan nuclear hormone receptor, ROR gamma lose thymic expression of the anti-apoptotic factor Bcl-xL. Ability of ROR gamma in inhibiting FAS ligand and cytokine gene expression; What causes the reduction of double positive thymocyte; Description of the T cells in ROR-gamma-deficient mice.

Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis.

Immunoglobulin A (IgA) production at mucosal surfaces contributes to protection against pathogens and controls intestinal microbiota composition. However, mechanisms regulating IgA induction are not completely defined. We show that soluble lymphotoxin α (sLTα3) produced by RORγt(+) innate lymphoid cells (ILCs) controls T cell-dependent IgA induction in the lamina propria via regulation of T cell homing to the gut. By contrast, membrane-bound lymphotoxin β (LTα1β2) produced by RORγt(+) ILCs is critical for T cell-independent IgA induction in the lamina propria via control of dendritic cell functions. Ablation of LTα in RORγt(+) cells abrogated IgA production in the gut and altered microbiota composition. Thus, soluble and membrane-bound lymphotoxins produced by ILCs distinctly organize adaptive immune responses in the gut and control commensal microbiota composition.

Interferon regulatory factor 4 (IRF4) and IRF8 regulate B, T, macrophage, and dendritic cell differentiation. They are recruited to cis-regulatory Ets-IRF composite elements by PU.1 or Spi-B. How these IRFs target genes in most T cells is enigmatic given the absence of specific Ets partners. Chromatin immunoprecipitation sequencing in T helper 17 (T(H)17) cells reveals that IRF4 targets sequences enriched for activating protein 1 (AP-1)-IRF composite elements (AICEs) that are co-bound by BATF, an AP-1 factor required for T(H)17, B, and dendritic cell differentiation. IRF4 and BATF bind cooperatively to structurally divergent AICEs to promote gene activation and T(H)17 differentiation. The AICE motif directs assembly of IRF4 or IRF8 with BATF heterodimers and is also used in T(H)2, B, and dendritic cells. This genomic regulatory element and cognate factors appear to have evolved to integrate diverse immunomodulatory signals.

Intestinal intraepithelial T lymphocytes (IELs) are likely to play a key role in host mucosal immunity and, unlike other T cells, have been proposed to differentiate from local precursors rather than from thymocytes. We show here that IELs expressing the alphabeta T cell receptor are derived from precursors that express RORgammat, an orphan nuclear hormone receptor detected only in immature CD4+CD8+ thymocytes, fetal lymphoid tissue-inducer (LTi) cells, and LTi-like cells in cryptopatches within the adult intestinal lamina propria. Using cell fate mapping, we found that all intestinal alphabeta T cells are progeny of CD4+CD8+ thymocytes, indicating that the adult intestine is not a significant site for alphabeta T cell development. Our results suggest that intestinal RORgammat+ cells are local organizers of mucosal lymphoid tissue.