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Tumors can evade conventional T cell recognition by rendering the HLA class I antigen presentation system defective. In a recent study, de Vries et al. reveal γδ T cells as key contributors to the efficacy of immune checkpoint blockade (ICB) against HLA-I-silenced cancers, highlighting a novel layer of surveillance against immune escape by tumors. [ABSTRACT FROM AUTHOR]

Special AT‐rich binding protein‐1 (SATB1) is a global chromatin organizer capable of activating or repressing gene transcription in mice and humans. The role of SATB1 is pivotal for T‐cell development, with SATB1‐knockout mice being neonatally lethal, although the exact mechanism is unknown. Moreover, SATB1 is dysregulated in T‐cell lymphoma and proposed to suppress transcription of the Pdcd1 gene, encoding the immune checkpoint programmed cell death protein 1 (PD‐1). Thus, SATB1 expression in T‐cell subsets across different tissue compartments in humans is of potential importance for targeting PD‐1. Here, we comprehensively analyzed SATB1 expression across different human tissues and immune compartments by flow cytometry and correlated this with PD‐1 expression. We investigated SATB1 protein levels in pediatric and adult donors and assessed expression dynamics of this chromatin organizer across different immune cell subsets in human organs, as well as in antigen‐specific T cells directed against acute and chronic viral infections. Our data demonstrate that SATB1 expression in humans is the highest in T‐cell progenitors in the thymus, and then becomes downregulated in mature T cells in the periphery. Importantly, SATB1 expression in peripheral mature T cells is not static and follows fine‐tuned expression dynamics, which appear to be tissue‐ and antigen‐dependent. Furthermore, SATB1 expression negatively correlates with PD‐1 expression in virus‐specific CD8+ T cells. Our study has implications for understanding the role of SATB1 in human health and disease and suggests an approach for modulating PD‐1 in T cells, highly relevant to human malignancies or chronic viral infections. [ABSTRACT FROM AUTHOR]

Abstract: Mucosal‐associated invariant T (MAIT) cells develop in the thymus and migrate into the periphery to become the largest antigen‐specific αβ T‐cell population in the human immune system. However, the frequency of MAIT cells varies widely between human individuals, and the basis for this is unclear. While MAIT cells are highly conserved through evolution and are phenotypically similar between humans and mice, they represent a much smaller proportion of total T cells in mice. In this review, we discuss how MAIT cells transition through a three‐stage development pathway in both mouse and human thymus, and continue to mature and expand after they leave the thymus. Moreover, we will explore and speculate on how specific factors regulate different stages of this process. [ABSTRACT FROM AUTHOR]

See also: Original Article by Winter et al. [ABSTRACT FROM AUTHOR]

Premature lymphocytes develop into non-autoreactive, mature naïve CD4+ or CD8+ T cells in the thymus before entering the circulation. However, in-depth characterization of human thymocyte development remains challenging due to limited availability of human thymus samples and the fragile nature of thymocyte populations. Thymocytes often do not survive cryopreservation and thawing procedures, especially the fragile CD4+CD8+ double positive population. It is generally recommended to use fresh human thymus tissue on the day of excision to avoid any biases in thymocyte composition. This hampers the possibility to perform multiple experiments on the same thymus sample. To establish how the thymocyte viability and composition can be maintained, we compared two thymocyte isolation methods used for human and/or mice thymi, three cryopreservation methods in combination with our most gentle thawing technique. Based on our findings we established that fresh human thymi remain viable in cold storage for up to two days post-surgery without compromising thymocyte composition. Thymocytes can be cryopreserved if required, although the CD4+CD8+ double positive populations may be reduced. Our study provides thoroughly optimized methods to study human thymocyte development over a considerable time-frame post-surgery. [ABSTRACT FROM AUTHOR]

Abstract: Mucosal‐associated invariant T (MAIT) cells represent up to 10% of circulating human T cells. They are usually defined using combinations of non‐lineage‐specific (surrogate) markers such as anti‐TRAV1‐2, CD161, IL‐18Rα and CD26. The development of MR1‐Ag tetramers now permits the specific identification of MAIT cells based on T‐cell receptor specificity. Here, we compare these approaches for identifying MAIT cells and show that surrogate markers are not always accurate in identifying these cells, particularly the CD4+ fraction. Moreover, while all MAIT cell subsets produced comparable levels of IFNγ, TNF and IL‐17A, the CD4+ population produced more IL‐2 than the other subsets. In a human ontogeny study, we show that the frequencies of most MR1 tetramer+ MAIT cells, with the exception of CD4+ MAIT cells, increased from birth to about 25 years of age and declined thereafter. We also demonstrate a positive association between the frequency of MAIT cells and other unconventional T cells including Natural Killer T (NKT) cells and Vδ2+ γδ T cells. Accordingly, this study demonstrates that MAIT cells are phenotypically and functionally diverse, that surrogate markers may not reliably identify all of these cells, and that their numbers are regulated in an age‐dependent manner and correlate with NKT and Vδ2+ γδ T cells. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are important for immune responses against microbial infections. Although known to undergo marked numerical changes with age in humans, our understanding of how MAIT cells are altered during different phases across the human life span is largely unknown. Although also abundant in the tissues, our study focuses on MAIT cell analyses in blood. Across the human life span, we show that naive-like MAIT cells in umbilical cord blood switch to a central/ effector memory-like profile that is sustained into older age. Whereas low-grade levels of plasma cytokine/chemokine were apparent in older donors (>65 y old), surprisingly, they did not correlate with the ex vivo MAIT hyperinflammatory cytokine profile observed in older adults. Removal of MAIT cells from older individuals and an aged environment resulted in the reversal of the baseline effector molecule profile comparable with MAIT cells from younger adults. An upregulated basal inflammatory profile accounted for reduced Escherichia coli-specific responses in aged MAIT cells compared with their young adult counterparts when fold change in expression levels of GzmB, CD107a, IFN-γ, and TNF was examined. However, the magnitude of antimicrobial MR1-dependent activation remained as potent and polyfunctional as with younger adults. Paired TCRab analyses of MAIT cells revealed large clonal expansions in older adults and tissues that rivalled, remarkably, the TCRαβ repertoire diversity of virus-specific CD8+ T cells. These data suggest that MAIT cells in older individuals, although associated with large clonal TCRαβ expansions and increased baseline inflammatory potential, demonstrate plasticity and provide potent antimicrobial immunity. [ABSTRACT FROM AUTHOR]

Invariant natural killer T cells (iNKT cells) are lipid-sensing innate T cells that are restricted by the antigen-presenting molecule CD1d and express the transcription factor PLZF. iNKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, as well as their targets in adipose tissue, are unknown. Here we found that iNKT cells in adipose tissue had a unique transcriptional program and produced interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lacked PLZF but expressed the transcription factor E4BP4, which controlled their IL-10 production. The adipose iNKT cells were a tissue-resident population that induced an anti-inflammatory phenotype in macrophages and, through the production of IL-2, controlled the number, proliferation and suppressor function of regulatory T cells (Treg cells) in adipose tissue. Thus, iNKT cells in adipose tissue are unique regulators of immunological homeostasis in this tissue. [ABSTRACT FROM AUTHOR]

Summary Glycosylceramides that activate CD1d-restricted invariant natural killer T ( i NKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of α-galactosylceramide as promising i NKT cell activators that stimulate cytokine responses with a strongly proinflammatory bias. However, the activities of sphinganine variants in mice have generally not translated well to studies of human i NKT cell responses. Here, we show that strongly proinflammatory and anti-tumor i NKT cell responses were achieved in mice by a variant of α-galactosylceramide that combines a sphinganine base with a hydrocinnamoyl ester on C6″ of the sugar. Importantly, the activities observed with this variant were largely preserved for human i NKT cell responses. Structural and in silico modeling studies provided a mechanistic basis for these findings and suggested basic principles for capturing useful properties of sphinganine analogs of synthetic i NKT cell activators in the design of immunotherapeutic agents. [ABSTRACT FROM AUTHOR]