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T lymphocytes are pivotal in adaptive immunity. The role of the trafficking protein particle complex (TRAPPC) in regulating T‐cell development and homeostasis is unknown. Using CD4cre‐Trappc1flox/flox (Trappc1 cKO) mice, we found that Trappc1 deficiency in T cells significantly decreased cell number of naive T cells in the periphery, whereas thymic T‐cell development in Trappc1 cKO mice was identical as WT mice. In the culture assays and mouse models with adoptive transfer of the sorted WT (CD45.1+CD45.2+) and Trappc1 cKO naive T cells (CD45.2+) to CD45.1+ syngeneic mice, Trappc1‐deficient naive T cells showed significantly reduced survival ability compared with WT cells. RNA‐seq and molecular studies showed that Trappc1 deficiency in naive T cells reduced protein transport from the endoplasmic reticulum to the Golgi apparatus, enhanced unfolded protein responses, increased P53 transcription, intracellular Ca2+, Atf4‐CHOP, oxidative phosphorylation, and lipid peroxide accumulation, and subsequently led to ferroptosis. Trappc1 deficiency in naive T cells increased ferroptosis‐related damage‐associated molecular pattern molecules like high mobility group box 1 or lipid oxidation products like prostaglandin E2, leukotriene B4, leukotriene C4, and leukotriene D4. Functionally, the culture supernatant of Trappc1 cKO naive T cells significantly promoted neutrophils to express inflammatory cytokines like TNFα and IL‐6, which was rescued by lipid peroxidation inhibitor Acetylcysteine. Importantly, Trappc1 cKO mice spontaneously developed severe autoinflammatory disease 4 weeks after birth. Thus, intrinsic expression of Trappc1 in naive T cells plays an integral role in maintaining T‐cell homeostasis to avoid proinflammatory naive T‐cell death‐caused autoinflammatory syndrome in mice. This study highlights the importance of the TRAPPC in T‐cell biology. [ABSTRACT FROM AUTHOR]

T‐bet is the lineage‐specifying transcription factor for CD4+ TH1 cells. T‐bet has also been found in other CD4+ T cell subsets, including TH17 cells and Treg, where it modulates their functional characteristics. However, we lack information on when and where T‐bet is expressed during T cell differentiation and how this impacts T cell differentiation and function. To address this, we traced the ontogeny of T‐bet‐expressing cells using a fluorescent fate‐mapping mouse line. We demonstrate that T‐bet is expressed in a subset of CD4+ T cells that have naïve cell surface markers and transcriptional profile and that this novel cell population is phenotypically and functionally distinct from previously described populations of naïve and memory CD4+ T cells. Naïve‐like T‐bet‐experienced cells are polarized to the TH1 lineage, predisposed to produce IFN‐γ upon cell activation, and resist repolarization to other lineages in vitro and in vivo. These results demonstrate that lineage‐specifying factors can polarize T cells in the absence of canonical markers of T cell activation and that this has an impact on the subsequent T‐helper response. [ABSTRACT FROM AUTHOR]

The survival of peripheral T cells is dependent on their access to peripheral LNs (pLNs) and stimulation by IL‐7. In pLNs fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs) produce IL‐7 suggesting their contribution to the IL‐7‐dependent survival of T cells. However, IL‐7 production is detectable in multiple organs and is not restricted to pLNs. This raises the question whether pLN‐derived IL‐7 is required for the maintenance of peripheral T cell homeostasis. Here, we show that numbers of naive T cells (TN) remain unaffected in pLNs and spleen of mice lacking Il7 gene activity in pLN FRCs, LECs, or both. In contrast, frequencies of central memory T cells (TCM) are reduced in FRC‐specific IL‐7 KO mice. Thus, steady state IL‐7 production by pLN FRCs is critical for the maintenance of TCM, but not TN, indicating that both T cell subsets colonize different ecological niches in vivo. [ABSTRACT FROM AUTHOR]

The role of mineralocorticoid receptors (MRs) in human T-cell migration is not yet understood. We have recently shown that the MR antagonist spironolactone selectively increases the numbers of circulating naïve and central memory T cells during early sleep, which is the time period in the 24 h cycle hallmarked by predominant MR activation. To investigate whether this effect is specific to spironolactone's blockade of MRs and to study the underlying molecular mechanisms, healthy humans were given the selective MR-agonist fludrocortisone or placebo and numbers of eight T-cell subsets and their CD62L and CXCR4 expression were analyzed. Fludrocortisone selectively reduced counts of naïve CD4+, central memory CD4+, and naïve CD8+ T cells and increased CXCR4 expression on the naïve subsets. In complementing in vitro studies, fludrocortisone enhanced CXCR4 and CD62L expression, which was counteracted by spironolactone. Incubation of naïve T cells with spironolactone alone reduced CD62L and CCR7 expression. Our results indicate a regulatory influence of MR signaling on human T-cell migration and suggest a role for endogenous aldosterone in the redistribution of T-cell subsets to lymph nodes, involving CD62L, CCR7, and CXCR4. Facilitation of T-cell homing following sleep-dependent aldosterone release might thus essentially contribute to sleep's well-known role in supporting adaptive immunity. [ABSTRACT FROM AUTHOR]

Following antigen encounter and subsequent resolution of the immune response, a single naïve T cell is able to generate multiple subsets of memory T cells with different phenotypic and functional properties and gene expression profiles. Single-cell technologies, first and foremost flow cytometry, have revealed the complex heterogeneity of the memory T-cell compartment and its organization into subsets. However, a consensus has still to be reached, both at the semantic (nomenclature) and phenotypic level, regarding the identification of these subsets. Here, we review recent developments in the characterization of the heterogeneity of the memory T-cell compartment, and propose a unified classification of both human and nonhuman primate T cells on the basis of phenotypic traits and in vivo properties. Given that vaccine studies and adoptive cell transfer immunotherapy protocols are influenced by these recent findings, it is important to use uniform methods for identifying and discussing functionally distinct subsets of T cells. [ABSTRACT FROM AUTHOR]

Current protocols used to select CMV-specific T cells for adoptive immunotherapy focus on virus-specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem-cell transplantation ( HSCT) from CMV-seronegative donors. Here, we redirected T cells of CMV-seronegative donors with a human genetically engineered TCR recognizing an HLA- A*0201-binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non-viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naïve-derived T-cell subsets were both efficiently transfected by TCR- RNA, memory-derived T cells showed much stronger levels of HLA- A*0201-restricted cytolytic activity to CMV-infected fibroblasts and maintained acquired function for 5-10 days. In addition to redirection of CD8+ cytotoxic T cells, TCR-RNA transfection was capable of redirecting CD4+ T cells into potent Ag-specific Th cells that efficiently triggered maturation of DCs. Our data suggest that memory rather than naïve-derived T cells are the preferred subset for transient TCR expression by RNA electroporation, providing more efficient and sustained virus-specific CD4+ and CD8+ T-cell function. CMV TCR- RNA may represent a suitable therapeutic 'off-the-shelf' reagent to be used in severe CMV infections of HSCT patients when endogenous CMV-specific T-cell immunity is insufficient. [ABSTRACT FROM AUTHOR]

T-bet is the lineage-specifying transcription factor for CD4 + T H 1 cells. T-bet has also been found in other CD4 + T cell subsets, including T H 17 cells and Treg, where it modulates their functional characteristics. However, we lack information on when and where T-bet is expressed during T cell differentiation and how this impacts T cell differentiation and function. To address this, we traced the ontogeny of T-bet-expressing cells using a fluorescent fate-mapping mouse line. We demonstrate that T-bet is expressed in a subset of CD4 + T cells that have naïve cell surface markers and transcriptional profile and that this novel cell population is phenotypically and functionally distinct from previously described populations of naïve and memory CD4 + T cells. Naïve-like T-bet-experienced cells are polarized to the T H 1 lineage, predisposed to produce IFN-γ upon cell activation, and resist repolarization to other lineages in vitro and in vivo. These results demonstrate that lineage-specifying factors can polarize T cells in the absence of canonical markers of T cell activation and that this has an impact on the subsequent T-helper response., (© 2022 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)