Reciprocal transmission of activating and inhibitory signals and cell fate in regenerating T cells.

The ability of activated progenitor T cells to self-renew while producing differentiated effector cell descendants may underlie immunological memory and persistent responses to ongoing infection. The nature of stem-like T cells responding to cancer and during treatment with immunotherapy is not clear. The subcellular organization of dividing progenitor CD8 T cells from mice challenged with syngeneic tumors is examined here.

PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors.

PD-1TCF-1 stem-like CD8 T cells act as critical resource cells for maintaining T cell immunity in chronic viral infections and cancer. In addition, they provide the proliferative burst of effector CD8 T cells after programmed death protein 1 (PD-1)-directed immunotherapy. However, it is not known whether checkpoint blockade diminishes the number of these stem-like progenitor cells as effector cell differentiation increases.

The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.

The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization.

Single-cell RNA sequencing reveals distinct T cell populations in immune-related adverse events of checkpoint inhibitors.

PD-1 is an inhibitory receptor in T cells, and antibodies that block its interaction with ligands augment anti-tumor immune responses. The clinical potential of these agents is limited by the fact that half of all patients develop immune-related adverse events (irAEs). To generate insights into the cellular changes that occur during anti-PD-1 treatment, we performed single-cell RNA sequencing of circulating T cells collected from patients with cancer.

Self-Renewing CD8+ T-cell Abundance in Blood Associates with Response to Immunotherapy.

Treatment with immune checkpoint blockade (ICB) often fails to elicit durable antitumor immunity. Recent studies suggest that ICB does not restore potency to terminally dysfunctional T cells, but instead drives proliferation and differentiation of self-renewing progenitor T cells into fresh, effector-like T cells. Antitumor immunity catalyzed by ICB is characterized by mobilization of antitumor T cells in systemic circulation and tumor.

Gastric Cancer and the Immune System: The Key to Improving Outcomes?

Gastric adenocarcinoma is by far the most common form of gastric cancer (GC) and is a highly lethal form of cancer arising from the gastric epithelium. GC is an important area of focus of the medical community, given its often late-stage of diagnosis and associated high mortality rate. While surgery and chemotherapy remain the primary treatments, attention has been drawn to the use of immunologic therapies, which have shown promise in the treatment of other malignancies.

Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome.

How intestinal microbes regulate metabolic syndrome is incompletely understood. We show that intestinal microbiota protects against development of obesity, metabolic syndrome, and pre-diabetic phenotypes by inducing commensal-specific Th17 cells. High-fat, high-sugar diet promoted metabolic disease by depleting Th17-inducing microbes, and recovery of commensal Th17 cells restored protection.

Cutting Edge: Promoting T Cell Factor 1 T Cell Self-Renewal to Improve Programmed Cell Death Protein 1 Blockade.

Immune checkpoint blockade is limited by resistance to treatment, with many patients not achieving durable antitumor responses. Self-renewing (T cell factor 1 [TCF1]) CD8 T cells have recently been implicated in efficacy of anti-programmed cell death protein 1 (anti-PD-1). Mice challenged with syngeneic tumors were treated with anti-PD-1 and/or a reversible inhibitor of PI3K δ, designed to promote T cell self-renewal.

The performance during four stationary knife attacks: Implications for tactical training.

Unlabelled: With over 72,000 offenses between 2010 and 2020 in the USA, knives were the third most commonly used weapon in all violent crimes between behind personal weapons and handguns.

Purpose: Examine the performance of different stab (Thrust and overhead) and slash (Figure 8 and Reverse) knife motions to determine how long it takes to execute each motion. In addition, examine the variability in executing each motion to inform future self-defense strategies.

A Regenerative Perspective on Successful and Failed T-Cell Immunity.

Heightened immunity after a primary infection, persistent control of low-level infection, or vanquished immunity from chronic-active infection and cancer are interrelated issues concerning the nature of T-cell regeneration during immunity. For many regenerating tissues and cellular systems, such as epithelia and blood, there are at least three distinguishable stages of development and repair, marked by progressive loss of self-renewal and progressive commitment to differentiation. T cells seem to be no different.

Inhibitory signaling sustains a distinct early memory CD8 T cell precursor that is resistant to DNA damage.

The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8 T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1 pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity.

Functional heterogeneity of human tissue-resident memory T cells based on dye efflux capacities.

Tissue-resident memory T cells (TRMs) accelerate pathogen clearance through rapid and enhanced functional responses in situ. TRMs are prevalent in diverse anatomic sites throughout the human lifespan, yet their phenotypic and functional diversity has not been fully described. Here, we identify subpopulations of human TRMs based on the ability to efflux fluorescent dyes [efflux(+) TRMs] located within mucosal and lymphoid sites with distinct transcriptional profiles, turnover, and functional capacities.

Transient T-bet expression functionally specifies a distinct T follicular helper subset.

T follicular helper (Tfh) cells express transcription factor BCL-6 and cytokine IL-21. Mature Tfh cells are also capable of producing IFN-γ without expressing the Th1 transcription factor T-bet. Whether this IFN-γ-producing Tfh population represents a unique Tfh subset with a distinct differentiation pathway is poorly understood.

TCF1 expression marks self-renewing human CD8 T cells.

Expression of the transcription factor T-cell factor 1 (TCF1) identifies antigen-experienced murine CD8 T cells that retain potential for lymphoid recirculation and the ability to self-renew while producing more differentiated effector cells. We found that CD8 T cells in the blood of both healthy and chronically infected humans expressed TCF1 at 3 distinct levels: high (TCF1-hi), intermediate (TCF1-int), and low (TCF1-lo). TCF1-hi cells could be found within both the naive and memory compartments and were characterized by relative quiescence and lack of immediate effector function.

Clonal Bifurcation of Foxp3 Expression Visualized in Thymocytes and T Cells.

Regulatory T cells (Tregs) are crucial for suppressing autoimmunity and inflammation mediated by conventional T cells. To be useful, some Tregs should have overlapping specificity with relevant self-reactive or pathogen-specific clones. Whether matching recognition between Tregs and non-Tregs might arise through stochastic or deterministic mechanisms has not been addressed.

Metabolic control of cell fate bifurcations in a hematopoietic progenitor population.

Growth signals drive hematopoietic progenitor cells to proliferate and branch into divergent cell fates, but how unequal outcomes arise from a common progenitor is not fully understood. We used steady-state analysis of in vivo hematopoiesis and Fms-related tyrosine kinase 3 ligand (Flt3L)-induced in vitro differentiation of dendritic cells (DCs) to determine how growth signals regulate lineage bias. We found that Flt3L signaling induced anabolic activation and proliferation of DC progenitors, which was associated with DC differentiation.

Cutting Edge: Divergent Requirement of T-Box Transcription Factors in Effector and Memory NK Cells.

The T-box transcription factors T-bet and Eomesodermin (Eomes) instruct discrete stages in NK cell development. However, their role in the immune response of mature NK cells against pathogens remains unexplored. We used an inducible deletion system to elucidate the cell-intrinsic role of T-bet and Eomes in mature NK cells during the course of mouse CMV infection.

Asymmetric PI3K Activity in Lymphocytes Organized by a PI3K-Mediated Polarity Pathway.

Unequal transmission of nutritive signaling during cell division establishes fate disparity between sibling lymphocytes, but how asymmetric signaling becomes organized is not understood. We show that receptor-associated class I phosphatidylinositol 3-kinase (PI3K) signaling activity, indexed by phosphatidylinositol (3,4,5)-trisphosphate (PIP) staining, is spatially restricted to the microtubule-organizing center and subsequently to one pole of the mitotic spindle in activated T and B lymphocytes. Asymmetric PI3K activity co-localizes with polarization of antigen receptor components implicated in class I PI3K signaling and with facultative glucose transporters whose trafficking is PI3K dependent and whose abundance marks cells destined for differentiation.

An Immunotherapeutic CD137 Agonist Releases Eomesodermin from ThPOK Repression in CD4 T Cells.

Agonists to the TNF/TNFR costimulatory receptors CD134 (OX40) and CD137 (4-1BB) elicit antitumor immunity. Dual costimulation with anti-CD134 plus anti-CD137 is particularly potent because it programs cytotoxic potential in CD8 and CD4 T cells. Cytotoxicity in dual-costimulated CD4 T cells depends on the T-box transcription factor eomesodermin (Eomes), which we report is induced via a mechanism that does not rely on IL-2, in contrast to CD8 CTL, but rather depends on the CD8 T cell lineage commitment transcription factor Runx3, which supports Eomes expression in mature CD8 CTLs.

IRF4 Couples Anabolic Metabolism to Th1 Cell Fate Determination.

Anabolic metabolism in lymphocytes promotes plasmablast and cytotoxic T cell differentiation at the expense of self-renewal. Heightened expression and function of the transcription factor IFN regulatory factor 4 (IRF4) accompany enhanced anabolic induction and full commitment to functional differentiation in B cells and CD8 T cells. In this study, we used a genetic approach to determine whether IRF4 plays an analogous role in Th1 cell induction.

Lymphocyte Fate and Metabolism: A Clonal Balancing Act.

Activated lymphocytes perform a clonal balancing act, yielding a daughter cell that differentiates owing to intense PI3K signaling, alongside a self-renewing sibling cell with blunted anabolic signaling. Divergent cellular anabolism versus catabolism is emerging as a feature of several developmental and regenerative paradigms. Metabolism can dictate cell fate, in part, because lineage-specific regulators are embedded in the circuitry of conserved metabolic switches.

[Effectivity of Inpatient Psychosomatic Treatment - Results of a Naturalistic Two-Year Survey in a Psychosomatic Service at a General Hospital].

Background: Hospital psychosomatic treatment matches care expectations of a modern society. Evidence of its effectiveness through investigation in different settings is of importance because of prominent role of psychotherapy in German Healthcare System.

Objective: First, to explore whether clinical as well as personal resources could improve significantly due to a hospital psychosomatic treatment.