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Two recent papers from the laboratory of Professor Ming Li demonstrate that inhibition of transforming growth factor specifically in CD4 SP + sp T cells can suppress tumor growth through an unanticipated mechanism. In their paper, Liu I et al i .5 provide an unanticipated explanation for why inhibition of TGF signaling in CD4 SP + sp T cells inhibits tumor growth. Strikingly, this effect was I completely independent i of CD8 SP + sp T cells, suggesting that TGF inhibition in CD4 SP + sp T cells acts through a mechanism unrelated to a T-helper cell-mediated promotion of CD8 SP + sp T-cell immunity. [Extracted from the article]

Effective vaccines have reduced the morbidity and mortality caused by severe acute respiratory syndrome coronavirus‐2 infection; however, the elderly remain the most at risk. Understanding how vaccines generate protective immunity and how these mechanisms change with age is key for informing future vaccine design. Cytotoxic CD8+ T cells are important for killing virally infected cells, and vaccines that induce antigen‐specific CD8+ T cells in addition to humoral immunity provide an extra layer of immune protection. This is particularly important in cases where antibody titers are suboptimal, as can occur in older individuals. Here, we show that in aged mice, spike epitope–specific CD8+ T cells are generated in comparable numbers to younger animals after ChAdOx1 nCoV‐19 vaccination, although phenotypic differences exist. This demonstrates that ChAdOx1 nCoV‐19 elicits a good CD8+ T‐cell response in older bodies, but that typical age‐associated features are evident on these vaccine reactive T cells. [ABSTRACT FROM AUTHOR]

Afterward, N SB 52-59 sb -specific T cells were fluorescence-activated cell sorting-based isolated from the spleen and transferred to new hosts bearing the CD45.2 genetic marker, to facilitate discrimination between transferred antigen-specific T cells and I de novo i -generated host antigen-specific T cells. Keywords: adaptive immunity; immune memory; memory T-cell; T-cell EN adaptive immunity immune memory memory T-cell T-cell 374 376 3 05/03/23 20230501 NES 230501 T-cell memory is considered long-lasting, but new evidence recently published in I Nature i by Soerens I et al i . shows that, under certain conditions, mouse memory T-cell immunity can span several mouse lifetimes. Age is just a number: long-lasting T-cell immunity can span several lifetimes. [Extracted from the article]

Almost 20 years ago, CD1d tetramers were developed to track invariant natural killer T (NKT) cells based on their specificity, and to define developmental steps during which differentiation markers and functional features are progressively acquired from early NKT cell precursor to fully mature NKT cell subsets. Based on these findings, a linear developmental model was proposed and subsequently used by all studies investigating the specific role of factors that control NKT cell development. More recently, based on intracellular staining patterns of lineage‐specific transcription factors such as T‐bet, GATA‐3, promyelocytic leukemia zinc finger and RORγt, a lineage differentiation model was proposed for NKT cell development. Currently, studies on NKT cells development present lineage differentiation model data in addition to the linear maturation model. In the perspective presented here, we discuss current knowledge relating to NKT cell developmental models and particularly focus on the approaches and strategies, some of which appear nebulous, used to define NKT cell developmental stages and subsets. [ABSTRACT FROM AUTHOR]

T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin‐related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F‐actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3‐knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon‐like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three‐dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3‐dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities. [ABSTRACT FROM AUTHOR]

Interleukin-18 (IL-18) is a cytokine with tumor-suppressing and tumor-promoting functions depending on the immune cell context. These include tumor-targeted delivery of immunocytokines (antibody-cytokine fusion proteins),[5] a mutant IL-2 preferentially activating cytotoxic lymphocytes[6] and cytokine-secreting chimeric antigen receptor T cells.[7] IL-18 was originally identified as an IFN -inducing factor. Compared with chimeric antigen receptor-T-cell therapies and bispecific T-cell engagers, it is not common to observe cytokine release syndrome/macrophage activation syndrome in patients treated with immune checkpoint blocking antibodies, but the risk might be increased by prolonged DRIL-18 treatment. [Extracted from the article]

Keywords: CD8 T cell; immunosenescence; leishmania; NK cell; NKG2D; sestrin EN CD8 T cell immunosenescence leishmania NK cell NKG2D sestrin 431 433 3 07/03/20 20200701 NES 200701 In Covre I et al. i and Pereira I et al i ., the authors demonstrate the parallels between senescent NK cells and senescent CD8 T cells, and formalise the mechanism by which senescent CD8 T cells become more NK cell-like, through the action of sestrins. Given that these senescence features are shared across NK cells and CD8 SP + sp T cells and they emerge at the same time across these populations, it is very likely that a common mechanism could drive senescence in each cell type. Finally, while sestrins mediate senescence and NK cell-like functions in CD8 SP + sp T cell, the mechanism that underpins senescence in NK cells is unclear. [Extracted from the article]

Natural killer T (NKT) cells were first recognized more than two decades ago as a distinct lymphocyte lineage that regulates a broad range of immune responses. The activation of NKT cells paradoxically can lead to either suppression or stimulation of immune responses, but despite this uncertainty, many investigators are hopeful that immune therapies can be developed based on NKT cell modulation. To date, the biology of NKT cells is not well characterized and details of their development have only just started to emerge. It remains unclear how NKT cells migrate from the thymus to the peripheral organs and tissues, and in turn play such diverse roles from one type of immune response to another. Despite this, recent advances in intravital microscopy represent a powerful tool for revealing new insights into NKT cellular dynamics, their patrolling and immunoregulatory functions, which could not have been gained by non-microscopy means. Indeed, imaging has revolutionized the way we visualize with exceptional resolution the cells of the immune system. Instead of seeking a comprehensive review of NKT cell biology, this review attempts to highlight some of the recent studies that use in vivo imaging technologies to address NKT cell responses in a variety of animal models. [ABSTRACT FROM AUTHOR]

Targeting CD40, a member of the tumor necrosis factor superfamily, using agonist antibodies (Abs) produces dramatic antitumor effects. Indeed, high-dose intravenous anti-CD40 Ab 'licenses' dendritic cells (DCs) that instruct activated CD8+ cytotoxic T cells to leave lymph nodes (LNs) and penetrate the mesothelioma tumor microenvironment. However, toxic side effects and the potential of an 'overwhelmed' immune response warrant an alternative approach. In this study, we show that injecting lower doses of anti-CD40 Ab directly into the tumor bed avoided toxic side effects and prolonged survival in 60% of mice, with most cured. Unexpectedly, DCs in tumors and LNs 'disappeared', CD8+ tumor-specific T-cell numbers and function were not enhanced, and T cells did not infiltrate regressing tumors. CD4+ or CD8+ depletion only marginally hindered anti-CD40 Ab efficacy implying another effector mechanism. B-cell numbers significantly increased in tumors, draining LNs and spleens during intratumoral anti-CD40 Ab treatment. CD40 targeting had no effect on splenic B-1 cells, obliterated marginal zone B cells and promoted follicular (FO) B-cell activity. Adoptive transfer of tumor antigen-experienced, CD40-activated B cells, or their immunoglobulin products, which recognized autoantigens on mesothelioma cells, protected against tumor challenge. Finally, studies using B-cell knockout mice showed that successful treatment of established tumors required the presence of B cells. Thus, these data suggest that CD40-activated FO B cells can become an important component of an effective antitumor immune response. [ABSTRACT FROM AUTHOR]