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The molecular mechanisms responsible for the high immunosuppressive capacity of [CD4.sup.+] Tregs in tumors are not well known. High-dimensional single-cell profiling of T cells from chemotherapy-naive individuals with non-small-cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral [CD4.sup.+] effector Tregs with superior suppressive activity. In contrast to the [IRF4.sup.-] counterparts, [IRF4.sup.+] Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespective of the tumor type., Introduction Despite recent clinical breakthroughs in adoptive T cell transfer approaches and checkpoint blockade in treating hematopoietic and solid tumors, suppression of the antitumor immune response in the tumor microenvironment [...]

Keywords: Editorials; CD8-positive T-lymphocytes; chemokines; immune checkpoint inhibitors; immunotherapy; myocarditis EN Editorials CD8-positive T-lymphocytes chemokines immune checkpoint inhibitors immunotherapy myocarditis 336 338 3 07/25/22 20220726 NES 220726 Immune checkpoint inhibitor (ICI) therapy for tumors is a life-saving treatment, yet occasionally patients experience ICI-induced myocarditis, an immune-mediated adverse reaction that is frequently lethal. ICI myocarditis is an urgent clinical problem, both for the patients experiencing the cardiac symptoms, and for the oncological patients, as well, whose access to novel ICIs may be experiencing delays linked to slower drug development that has to keep ICI myocarditis in mind. [Extracted from the article]

Abstract: Heart failure (HF), the final stage of pathological cardiac hypertrophy, is a major cause of hospitalization and mortality. The role of inflammation in the pathogenesis of HF has been extensively studied, with great emphasis on proinflammatory cytokines. Yet, clinical trials targeting these cytokines failed to become a credible therapeutic strategy for HF. More recent studies are increasingly highlighting an active role for T cells in the progression of HF pathology. As a result, a number of novel immunotherapy strategies are emerging for the treatment of HF and other cardiovascular diseases, via the targeting of adaptive immunity. Here we provide an overview of the background, details, and expected outcomes of these attempts. [ABSTRACT FROM AUTHOR]

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Cytotoxic T lymphocytes (cytotoxic T cells, CTLs) are an immune effector cell population that can mediate specific immune responses against cancer. Based on this concept, tumor immunotherapy protocols have been developed using adoptive transfer of in vitro -expanded autologous T cells that can kill cancer cells. However, fully functional adoptive T cell therapies (ACT) are hampered by the inability to guarantee that all transferred T cells manage to reach the tumor sites and make contact with cancer cells. The lack of tumor homing of T cells may be caused by a variety of reasons. Stromal architecture and biological features of the tumor microenvironment may act as barriers to T cell migration. A mismatch between the chemokines released by the tumor or tumor stroma and the chemokine receptors expressed on the transferred T cells may also impede T cell homing. The identification of mechanisms responsible for cancer stroma remodeling is helping to overcome the barriers of access to tumors, via novel therapeutic strategies targeting tumor-stroma interactions. Simultaneously, recent studies have demonstrated ways through which virally-transduced CTLs can be made to express suitable chemokine receptors so as to enhance ACT, by improving CTL homing into the tumor. Here we review the most important findings related to T cell trafficking to the tumor, highlighting contributions that have led to promising improvements in the available T cell therapy strategies. We discuss new possible combinatorial strategies aimed to overcome chemokine mismatch, physical and biological barriers and immunosuppression, so as to achieve more effective ACT therapies. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 4,5-biphosphate (PIP2) is critical for T lymphocyte activation serving as a substrate for the generation of second messengers and the remodeling of actin cytoskeleton necessary for the clustering of lipid rafts, TCR, and costimulatory receptors toward the T:APC interface. Spatiotemporal analysis of PIP2 synthesis in T lymphocytes suggested that distinct isoforms of the main PIP2-generating enzyme, phosphatidylinositol 4-phosphate 5-kinase (PIP5K), play a differential role on the basis of their distinct localization. In this study, we analyze the contribution of PIP5Kβ to T cell activation and show that CD28 induces the recruitment of PIP5Kβ to the immunological synapse, where it regulates filamin A and lipid raft accumulation, as well as T cell activation, in a nonredundant manner. Finally, we found that Vav1 and the C-terminal 83 aa of PIP5Kβ are pivotal for the PIP5Kβ regulatory functions in response to CD28 stimulation. [ABSTRACT FROM AUTHOR]

The primary event for initiating adaptive immune responses is the encounter between T lymphocytes and antigen presenting cells (APCs) in the T cell area of secondary lymphoid organs and the formation of highly organized intercellular junctions referred to as immune synapses (IS). In vivo live-cell imaging of APC-T cell interactions combined to functional studies unveiled that T cell fate is dictated, in large part, by the stability of the initial contact. Immune cell interaction is equally important during delivery of T cell help to B cells and for the killing of target cells by cytotoxic T cells and NK cells. The critical role of contact dynamics and synapse stability on the immune response is well illustrated by human immune deficiencies in which disease pathogenesis is linked to altered adhesion or defective cross-talk between the synaptic partners. The Wiskott-Aldrich syndrome (WAS) is a severe primary immunodeficiency caused by mutations in the Wiskott-Aldrich syndrome protein (WASp), a scaffold that promotes actin polymerization and links TCR stimulation to T cell activation. Absence or mutations in WASp affects intercellular APC-T cell communications by interfering with multiple mechanisms on both sides of the IS. The warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is caused by mutations in CXCR4, a chemokine receptor that in mutant form leads to impairment of APC-T cell interactions. Present evidences suggest that other recently characterized primary immune deficiencies caused by mutation in genes linked to actin cytoskeletal reorganization, such as WIP and DOCK8, may also depend on altered synapse stability. Here, we will discuss in details the mechanisms of disturbed APC-T cell interactions in WAS and WHIM. Moreover, we will summarize the evidence pointing to a compromised conjugate formation in WIP, DOCK8, and X-linked lymphoproliferative syndrome. [ABSTRACT FROM AUTHOR]

WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome is a rare disease characterized by diverse symptoms indicative of aberrantly functioning immunity. It is caused by mutations in the chemokine receptor CXCR4, which impair its intracellular trafficking, leading to increased responsiveness to chemokine ligand and retention of neutrophils in bone marrow. Yet WHIM symptoms related to adaptive immunity, such as delayed IgG switching and impaired memory B-cell function, remain largely unexplained. We hypothesized that the WHIM-associated mutations in CXCR4 may affect the formation of immunologic synapses between T cells and antigen-presenting cells (APCs). We show that, in the presence of competing external chemokine signals, the stability of T-APC conjugates from patients with WHIM-mutant CXCR4 is disrupted as a result of impaired recruitment of the mutant receptor to the immunologic synapse. Using retrogenic mice that develop WHIM-mutant T cells, we show that WHIM-mutant CXCR4 inhibits the formation of long-lasting T-APC interactions in ex vivo lymph node slice time-lapse microscopy. These findings demonstrate that chemokine receptors can affect T-APC synapse stability and allow us to propose a novel mechanism that contributes to the adaptive immune response defects in WHIM patients [ABSTRACT FROM AUTHOR]

Problem Is the concept of maternal tolerance preventing rejection of the semi-allogeneic ‘fetal allograft’ still valid? Method of study Compilation of expert reviews of literature and recent advances in research on indoleamine-2,3 dioxygenase (IDO), regulatory T cells and galectin-1. Results and Conclusion A role for IDO in pregnancy success remains speculative, but solid data exist to support a role for Treg cells, and for galectin-1 in induction and action of Treg cells. Just as several signals may need to be simultaneously present to induce Th1 cytokine-triggered abortions, more than 1 signal may need to be simultaneously present to prevent rejection and ensure success. Both complement and coagulation pathways appear necessary for embryo execution. [ABSTRACT FROM AUTHOR]

Regulatory T cells play an essential role in preventing fetal rejection by the maternal immune system. Here we show that, based on the expression of CCR5, regulatory T cells can be divided into a highly suppressive CCR5+ and a far less suppressive CCRS- sub-population, suggesting that the former represent the effector arm of regulatory T cells. Although regulatory T ceils from CCR5-/- gene deletion mutants still suppress, they are less effective mediators of maternal-fetal tolerance. The accumulation of CCR5+ regulatory T cells at this site appears to be enhanced by alloantigen. This finding is in stark contrast to the systemic expansion of regulatory T cells during pregnancy, which appears to be alloantigen-independent. The fact that CCR5+ regulatory T cells preferentially accumulate in the gravid uterus and that expression of CCR5 on regulatory T cells can be induced by activation lead us to propose that CCR5 is responsible for the accumulation of those regulatory T cells that have been activated by paternal antigens. [ABSTRACT FROM AUTHOR]

Pregnancy constitutes a major challenge to the maternal immune system, as it has to tolerate the persistence of paternal alloantigen. Although localized mechanisms contribute to fetal evasion from immune attack, maternal alloreactive lymphocytes persist. We demonstrate here an alloantigen-independent, systemic expansion of the maternal CD25+ T cell pool during pregnancy and show that this population contains dominant regulatory T cell activity. In addition to their function in suppressing autoimmune responses, maternal regulatory T cells suppressed an aggressive allogeneic response directed against the fetus. Their absence led to a failure of gestation due to immunological rejection of the fetus. [ABSTRACT FROM AUTHOR]

Abstract: Pregnancy frequently has a beneficial effect on the autoimmune disease Rheumatoid Arthritis, ranging from improvement in clinical symptoms to complete remission. Despite decades of study, a mechanistic explanation remains elusive. Here, we demonstrate that an analogous pregnancy-induced remission can be observed in a mouse model of arthritis. We demonstrate that during pregnancy mice are protected from collagen-induced arthritis, but are still capable of launching normal immune responses to influenza infections. We examine the role of regulatory T (TR) cells in this beneficial effect. TR cells are essential for many aspects of immune tolerance, including the suppression of autoimmune responses. Remarkably, transfer of regulatory T cells from pregnant ‘protected’ mice was sufficient to confer protection to non-pregnant mice. These results suggest that regulatory T cells are responsible for the pregnancy-induced amelioration of arthritis. [Copyright &y& Elsevier]

Regulatory T cells (Treg) influence the development of autoimmunity and their use is increasingly proposed for clinical applications. The well-characterized suppressive potential of Treg frequently leads to the assumption that Treg presence in prevailing numbers is indicative of immunosuppression. We hypothesized that this assumption may be false. We examined models of three different diseases caused by organ-specific autoimmune responses: primary biliary cirrhosis, atherosclerosis and rheumatoid arthritis (RA). We examined indicators of relative abundance of Treg compared to pro-inflammatory T cells, during peak inflammation. In all cases, the results were compatible with a relative enrichment of Treg at the site of inflammation or its most proximal draining lymph node. Conversely, in healthy mice or mice successfully protected from disease via a Treg-mediated mechanism, the data did not suggest that any Treg accumulation was occurring. This counter-intuitive finding may appear to be at odds with the immunosuppressive nature of Treg. Yet extensive previous studies in RA show that an accumulation of Treg occurs at peak inflammation, albeit without resulting in suppression, as the Treg suppressive function is overcome by the cytokine-rich environment. We suggest that this is a ubiquitous feature of autoimmune inflammation. Treg abundance in patient samples is increasingly used as an indicator of a state of immunosuppression. We conclude that this strategy should be revisited as it may potentially be a source of misinterpretation. [ABSTRACT FROM AUTHOR]