A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib-restricted CD8+ regulatory T cells.

Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination of pathogenic target cells that express these Qa-1-self-peptide complexes selectively inhibits pathogenic antibody responses without generalized immune suppression.

Associations of cortical SPP1 and ITGAX with cognition and common neuropathologies in older adults.

Introduction: The secreted phosphoprotein 1 (SPP1) gene expressed by CD11c cells is known to be associated with microglia activation and neuroinflammatory diseases. As most studies rely on mouse models, we investigated these genes and proteins in the cortical brain tissue of older adults and their role in Alzheimer's disease (AD) and related disorders.

Methods: We leveraged protein measurements, single-nuclei, and RNASeq data from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) of over 1200 samples for association analysis.

Antibody-mediated blockade of the IL23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy.

Regulatory T cells (Treg) can impede antitumor immunity and currently represent a major obstacle to effective cancer immunotherapy. Targeting tumor-infiltrating regulatory Treg while sparing systemic Treg represents an optimal approach to this problem. Here, we provide evidence that the interleukin 23 receptor (IL23R) expressed by tumor-infiltrating Treg promotes suppressive activity.

Definition of a mouse microglial subset that regulates neuronal development and proinflammatory responses in the brain.

Expression of (encoding the CD11c surface protein) and (encoding osteopontin; OPN) has been associated with activated microglia that can develop in healthy brains and some neuroinflammatory disorders. However, whether CD11c and OPN expression is a consequence of microglial activation or represents a portion of the genetic program expressed by a stable microglial subset is unknown. Here, we show that OPN production in the brain is confined to a small CD11c microglial subset that differentiates from CD11c precursors in perinatal life after uptake of apoptotic neurons.

From antibody specificity to T cell recognition.

Landsteiner's definition of human blood groups and the genetic rules that govern blood transfusion represents a milestone in human genetics and a historic event in public health. His research into the specificity of serological reactions, although less well known, has had a critical influence on the development of contemporary views on immune recognition, clonal selection, and immunological self-tolerance.

A new chapter in the CD8 T reg story.

CD8+ T reg cells play an important role in the maintenance of self-tolerance and can inhibit the development of autoimmune disease. In this issue of JEM, Mishra et al. (https://doi.

Overcoming Immune Checkpoint Blockade Resistance via EZH2 Inhibition.

Recent progress in cancer immunotherapy highlights the power of the immune system to control tumors, although a small patient subset responds to current immunotherapies. Additional approaches to mobilize antitumor immunity are required to overcome primary and acquired resistance to immunotherapy such as immune checkpoint blockade (ICB). Emerging evidence shows that targeting epigenetic elements that promote tumor progression and inhibit immune cell activity can enhance antitumor immunity by reshaping the tumor microenvironment (TME).

NK Cells Regulate CD8 T Cell Mediated Autoimmunity.

Elucidating key factors that regulate immune-mediated pathology is critical for developing improved strategies to treat autoimmune disease and cancer. NK cells can exhibit regulatory functions against CD8 T cells following viral infection. Here we show that while low doses of lymphocytic choriomeningitis virus (LCMV-WE) can readily induce strong CD8 T cell responses and diabetes in mice expressing the LCMV glycoprotein on β-islet cells (RIP-GP mice), hyperglycemia does not occur after infection with higher doses of LCMV.

Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts.

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts.

Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 Transcription Factor.

Follicular regulatory T (T) cells are a specialized suppressive subset that controls the germinal center (GC) response and maintains humoral self-tolerance. The mechanisms that maintain T lineage identity and suppressive activity remain largely unknown. Here, we show that expression of Blimp1 by FoxP3 T cells is essential for T lineage stability, entry into the GC, and expression of regulatory activity.

New Insights Into the Biology of CD8 Regulatory T Cells.

Regulatory T cells are central mediators of immune regulation and play an essential role in the maintenance of immune homeostasis in the steady state and under pathophysiological conditions. Disruption of CD8 Treg-dependent recognition of Qa-1-restricted self-antigens can result in dysregulated immune responses, tissue damage, autoimmune disease and cancer. Recent progress in studies on regulatory T cells of the CD8 lineage has provided new biological insight into this specialized regulatory T cell subpopulation.

Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells.

Lineage commitment and differentiation into CD4 T cell subsets reflect an interplay between chromatin regulators and transcription factors (TF). Follicular T cell development is regulated by the Bcl6 TF, which helps determine the phenotype and follicular localization of both CD4 follicular helper T cells (T) and follicular regulatory T cells (T). Here we show that Bcl6-dependent control of follicular T cells is mediated by a complex formed between Bcl6 and the Mi-2β-nucleosome-remodeling deacetylase complex (Mi-2β-NuRD).

Comparative transcriptome analysis reveals distinct genetic modules associated with Helios expression in intratumoral regulatory T cells.

Regulatory T cells (Tregs) are key modulators of immune tolerance, capable of suppressing inflammatory immune responses and promoting nonlymphoid tissue homeostasis. Helios, a transcription factor (TF) that is selectively expressed by Tregs, has been shown to be essential for the maintenance of Treg lineage stability in the face of inflammatory conditions that include autoimmune disease and cancer. Helios-deficient Tregs within tumors acquire effector T cell function and contribute to immune responses against cancer.

γδ T Cells Contribute to Injury in the Developing Brain.

Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurologic disabilities. Inflammation contributes to perinatal brain injury development, but the essential mediators that lead to early-life brain injury remain largely unknown. Neonates have reduced capacity for mounting conventional αβT-cell responses.

Lymphocytes Negatively Regulate NK Cell Activity via Qa-1b following Viral Infection.

NK cells can reduce anti-viral T cell immunity during chronic viral infections, including infection with the lymphocytic choriomeningitis virus (LCMV). However, regulating factors that maintain the equilibrium between productive T cell and NK cell immunity are poorly understood. Here, we show that a large viral load resulted in inhibition of NK cell activation, which correlated with increased expression of Qa-1b, a ligand for inhibitory NK cell receptors.

The microRNA miR-31 inhibits CD8 T cell function in chronic viral infection.

During infection, antigen-specific T cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. We found that the microRNA miR-31 was strongly induced by activation of the T cell antigen receptor (TCR) in a pathway involving calcium and activation of the transcription factor NFAT. During chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13, miR-31-deficent mice recovered from clinical disease, while wild-type mice continued to show signs of disease.

MHC Ib molecule Qa-1 presents Mycobacterium tuberculosis peptide antigens to CD8+ T cells and contributes to protection against infection.

A number of nonclassical MHC Ib molecules recognizing distinct microbial antigens have been implicated in the immune response to Mycobacterium tuberculosis (Mtb). HLA-E has been identified to present numerous Mtb peptides to CD8+ T cells, with multiple HLA-E-restricted cytotoxic T lymphocyte (CTL) and regulatory T cell lines isolated from patients with active and latent tuberculosis (TB). In other disease models, HLA-E and its mouse homolog Qa-1 can act as antigen presenting molecules as well as regulators of the immune response.

Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1.

T helper type 17 cells (Th17 cells) are major contributors to many autoimmune diseases. In this study, we demonstrate that the germinal center kinase family member MINK1 (misshapen/NIK-related kinase 1) negatively regulates Th17 cell differentiation. The suppressive effect of MINK1 on induction of Th17 cells is mediated by the inhibition of SMAD2 activation through direct phosphorylation of SMAD2 at the T324 residue.