Anti-PD-1 amplifies costimulation in melanoma-infiltrating T1-like Foxp3 regulatory T cells to alleviate local immunosuppression.

Background: Immune checkpoint inhibitors targeting programmed cell death protein-1 (PD-1) are the first line of treatment for many solid tumors including melanoma. PD-1 blockade enhances the effector functions of melanoma-infiltrating CD8 T cells, leading to durable tumor remissions. However, 55% of patients with melanoma do not respond to treatment.

The eIF4EBP-eIF4E axis regulates CD4 T cell differentiation through modulation of T cell activation and metabolism.

CD4 T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4 T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript.

IL-18 is required for the T1-adaptation of T cells and the selective suppression of T17 responses in acute and chronic infections.

Interleukin (IL)-18, a member of the IL-1 family of alarmins, is abundantly released in the lungs following influenza A (IAV) infections yet its role in orchestrating the local adaptive immune response remains ill defined. Through genetic disruption of the IL-18 receptor, we demonstrate that IL-18 not only promotes pulmonary T1 responses but also influences regulatory T cells (T) function in the infected lungs. As the response unfolds, T cells accumulating in the lungs express Helios, T-bet, CXCR3, and IL-18R1 and produce interferon γ in the presence of IL-12.

ICOS-Deficient Regulatory T Cells Can Prevent Spontaneous Autoimmunity but Are Impaired in Controlling Acute Inflammation.

ICOS is induced in activated T cells and its main role is to boost differentiation and function of effector T cells. ICOS is also constitutively expressed in a subpopulation of Foxp3 regulatory T cells under steady-state condition. Studies using ICOS germline knockout mice or ICOS-blocking reagents suggested that ICOS has supportive roles in regulatory T (Treg) cell homeostasis, migration, and function.

A Hemagglutinin 1 Carrying Plant-Based Virus-like Particle Vaccine Generates an Efficacious Cellular Response by Exploiting IL-1 Signaling in Both Adult and Aged Mice.

Inactivated influenza vaccines have struggled to provide consistent protection in older individuals. Circumventing immune senescence, an aging of the immune response characterized by weak humoral responses to vaccines, and unchecked inflammation during infection require novel immunization strategies. Plant-based virus-like particles (VLPs) bearing recombinant hemagglutinin proteins have been shown to provide protection in older animals in preclinical challenge studies, despite eliciting relatively low or absent humoral responses.

Salt Sensing by Serum/Glucocorticoid-Regulated Kinase 1 Promotes Th17-like Inflammatory Adaptation of Foxp3 Regulatory T Cells.

Regulatory T (Treg) cells integrate diverse environmental signals to modulate their function for optimal suppression. Translational regulation represents a favorable mechanism for Treg cell environmental sensing and adaptation. In this study, we carry out an unbiased screen of the Treg cell translatome and identify serum/glucocorticoid-regulated kinase 1 (SGK1), a known salt sensor in T cells, as being preferentially translated in activated Treg cells.

Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts.

Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases.

Liver metastases (LM) remain a major cause of cancer-associated death and a clinical challenge. Here we explore a sexual dimorphism observed in the regulation of the tumor immune microenvironment (TIME) of LM, wherein the accumulation of myeloid-derived suppressor cells (MDSC) and regulatory T cells in colon and lung carcinoma LM is TNFR2-dependent in female, but not in male mice. In ovariectomized mice, a marked reduction is observed in colorectal, lung and pancreatic carcinoma LM that is reversible by estradiol reconstitution.

The Deubiquitinating Enzyme Ubiquitin-Specific Peptidase 11 Potentiates TGF-β Signaling in CD4 T Cells to Facilitate Foxp3 Regulatory T and T17 Cell Differentiation.

Foxp3 regulatory T (T) cells are central mediators in the control of peripheral immune responses. Genome-wide transcriptional profiles show canonical signatures for Foxp3 T cells, distinguishing them from Foxp3 effector T (T) cells. We previously uncovered distinct mRNA translational signatures differentiating CD4 T and T cells through parallel measurements of cytosolic (global) and polysome-associated (translationally enhanced) mRNA levels in both subsets.

The alarmins IL-1 and IL-33 differentially regulate the functional specialisation of Foxp3 regulatory T cells during mucosal inflammation.

CD4Foxp3 regulatory T (T) cells are critical mediators of peripheral tolerance and modulators of immune responses. Functional adaptation of T cells, through acquisition of secondary transcription factors is critical for their effector differentiation towards local inflammatory stimuli including infections. The drivers and consequences of this adaptation of T cell function remain largely unknown.

CD4 Regulatory T Lymphocytes Prevent Impaired Cerebral Blood Flow in Angiotensin II-Induced Hypertension.

Background Immune cells are key regulators of the vascular inflammatory response characteristic of hypertension. In hypertensive rodents, regulatory T lymphocytes (Treg, CD 4 CD 25) prevented vascular injury, cardiac damage, and endothelial dysfunction of mesenteric arteries. Whether Treg modulate the cerebrovascular damage induced by hypertension is unknown.

Translational control in the tumor microenvironment promotes lung metastasis: Phosphorylation of eIF4E in neutrophils.

The translation of mRNAs into proteins serves as a critical regulatory event in gene expression. In the context of cancer, deregulated translation is a hallmark of transformation, promoting the proliferation, survival, and metastatic capabilities of cancer cells. The best-studied factor involved in the translational control of cancer is the eukaryotic translation initiation factor 4E (eIF4E).

KLRG1 expression identifies short-lived Foxp3 T effector cells with functional plasticity in islets of NOD mice.

A progressive waning in Foxp3 regulatory T (T) cell function provokes autoimmunity in the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D), a cellular defect rescued by prophylactic IL-2 therapy. We showed that most islet-infiltrating T cells express inducible T-cell co-stimulator (ICOS) in pre-diabetic NOD mice, and that ICOS T cells display enhanced fitness and suppressive function in situ. Moreover, T1D progression is associated with decreased expansion and suppressive activity of ICOSFoxp3 T cells, in islets, an observation consistent with the exacerbated T1D seen in NOD.

Suppression by human FOXP3 regulatory T cells requires FOXP3-TIP60 interactions.

CD4FOXP3 regulatory T (T) cells are critical mediators of immune tolerance, and their deficiency owing to mutations in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) patients results in severe autoimmunity. Different mutations result in a wide range of disease severity, reflecting the relative importance of the affected residues in the integrity of the FOXP3 protein and its various molecular interactions. We characterized the cellular and molecular impact of the most common IPEX mutation, p.

Posttranscriptional and Translational Control of Gene Regulation in CD4+ T Cell Subsets.

The immune system is under strict regulatory control to ensure homeostasis of inflammatory responses, lying dormant when not needed but quick to act when called upon. Small changes in gene expression can lead to drastic changes in lineage commitment, cellular function, and immunity. Conventional assessment of these changes centered on the analysis of mRNA levels through a variety of methodologies, including microarrays.