The hypoxic response in cells and tissues is mediated by the family of hypoxia-inducible factor (HIF) transcription factors; these play an integral role in the metabolic changes that drive cellular ...adaptation to low oxygen availability. HIF expression and stabilization in immune cells can be triggered by hypoxia, but also by other factors associated with pathological stress: e.g., inflammation, infectious microorganisms, and cancer. HIF induces a number of aspects of host immune function, from boosting phagocyte microbicidal capacity to driving T cell differentiation and cytotoxic activity. Cellular metabolism is emerging as a key regulator of immunity, and it constitutes another layer of fine-tuned immune control by HIF that can dictate myeloid cell and lymphocyte development, fate, and function. Here we discuss how oxygen sensing in the immune microenvironment shapes immunological response and examine how HIF and the hypoxia pathway control innate and adaptive immunity.
Hypoxia-inducible factor (HIF) transcription factors can be triggered by hypoxia and by other factors associated with pathological stress. Johnson and colleagues review the role of HIF and other key players in the hypoxic response in the control of innate and adaptive immunity.
Cytotoxic CD8
T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8
T cell ...metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programmes facilitate the adaptation of CD8
T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues. In the setting of disease, both cell-intrinsic and cell-extrinsic metabolic cues contribute to CD8
T cell dysfunction. In addition, changes in whole-body metabolism, whether through voluntary or disease-induced dietary alterations, can influence CD8
T cell-mediated immunity. Defining the metabolic adaptations of CD8
T cells in specific tissue environments informs our understanding of how these cells protect against pathogens and tumours and maintain tissue health at barrier sites. Here, we highlight recent findings revealing how metabolic networks enforce specific CD8
T cell programmes and discuss how metabolism is integrated with CD8
T cell differentiation and function and determined by environmental cues.
T follicular helper (Tfh) cells are essential in the induction of high-affinity, class-switched antibodies. The differentiation of Tfh cells is a multi-step process that depends upon the co-receptor ...ICOS and the activation of phosphoinositide-3 kinase leading to the expression of key Tfh cell genes. We report that ICOS signaling inactivates the transcription factor FOXO1, and a Foxo1 genetic deletion allowed for generation of Tfh cells with reduced dependence on ICOS ligand. Conversely, enforced nuclear localization of FOXO1 inhibited Tfh cell development even though ICOS was overexpressed. FOXO1 regulated Tfh cell differentiation through a broad program of gene expression exemplified by its negative regulation of Bcl6. Final differentiation to germinal center Tfh cells (GC-Tfh) was instead FOXO1 dependent as the Foxo1(-/-) GC-Tfh cell population was substantially reduced. We propose that ICOS signaling transiently inactivates FOXO1 to initiate a Tfh cell contingency that is completed in a FOXO1-dependent manner.
Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To accommodate increased bioenergetic and ...biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. In parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. Many chromatin- and DNA-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. In this review, we discuss recent studies of T cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and T cell responses to infection.
Pathogen detection induces gene expression and metabolic shifts in immune cells to facilitate effector programs. Phan, Goldrath, and Glass review emerging evidence that metabolic activity modulates “writers” and “erasers” of the epigenetic landscape and discuss how this may tailor tissue-specific activity of macrophages and T cells.
Immunological memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Here we highlight advances in the understanding of the diverse T lymphocyte subsets ...that provide acute and long-term protection from infection. These include new insights into the transcription factors, and the upstream 'pioneering' factors that regulate their accessibility to key sites of gene regulation, as well as metabolic regulators that contribute to the differentiation of effector and memory subsets; ontogeny and defining characteristics of tissue-resident memory lymphocytes; and origins of the remarkable heterogeneity exhibited by activated T cells. Collectively, these findings underscore progress in delineating the underlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge, as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cell responses through vaccination and immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Cytotoxic CD8+ T cells recognize and eliminate infected or cancerous cells. A subset of CD8+ memory T cells called tissue‐resident memory T cells (TRM) resides in peripheral tissues, monitors ...the periphery for pathogen invasion, and offers a rapid and potent first line of defense at potential sites of re‐infection. TRM cells are found in almost all tissues and are transcriptionally and epigenetically distinct from circulating memory populations, which shows their ability to acclimate to the tissue environment to allow for long‐term survival. Recent work and the broader availability of single‐cell profiling have highlighted TRM heterogeneity among different tissues, as well as identified specialized subsets within individual tissues, that are time and infection dependent. TRM cell phenotypic and transcriptional heterogeneity has implications for understanding TRM function and longevity. This review aims to summarize and discuss the latest findings on CD8+ TRM heterogeneity using single‐cell molecular profiling and explore the potential implications for immune protection and the design of immune therapies.
Extensive metabolic changes accompany T cell activation, including a switch to glycolytic energy production and increased biosynthesis. Recent studies suggest that subsequent return to reliance on ...oxidative phosphorylation and increasing spare respiratory capacity are essential for the differentiation of memory CD8+ T cells. In contrast, we found that constitutive glycolytic metabolism and suppression of oxidative phosphorylation in CD8+ T cells, achieved by conditional deletion of hypoxia-inducible factor regulator Vhl, accelerated CD8+ memory cell differentiation during viral infection. Despite sustained glycolysis, CD8+ memory cells emerged that upregulated key memory-associated cytokine receptors and transcription factors and showed a heightened response to secondary challenge. In addition, increased glycolysis not only permitted memory formation, but it also favored the formation of long-lived effector-memory CD8+ T cells. These data redefine the role of cellular metabolism in memory cell differentiation, showing that reliance on glycolytic metabolism does not hinder formation of a protective memory population.
•Increased SRC and a reliance on OXPHOS are not essential for memory CD8+ T cells•Glycolytic metabolism does not hinder differentiation of memory CD8+ T cells•Provision of ATP is paramount to metabolic pathway usage in effector T cell responses•Glycolytic metabolism may preferentially promote differentiation of Tem cells
Whether alterations in cellular metabolism correlate with or drive CD8+ T cell differentiation is unclear. Phan and colleagues demonstrate that memory T cell differentiation does not require generation of SRC or a switch to reliance on OXPHOS. Furthermore, glycolytic metabolism not only supports memory differentiation but may promote Tem cells.
In this issue of JEM, Qiu et al. (2023. J. Exp. Med. https://doi.org/10.1084/jem.20210923) show that retinoic acid signaling during priming in the mesenteric lymph node licenses CD8+ T cells to ...develop into small intestinal tissue-resident memory cells, a finding that provides key insights into tissue-specific vaccination strategies.
•TRM formation relies on a ‘hybrid’ program of effector and memory T cell TFs.•Differentiating TRM are transcriptionally distinct from circulating MP cells.•Blimp1, Hobit, and Runx3 are central ...regulators of immune cell tissue-residency.•Therapeutic manipulation of tissue-residency can be leveraged to treat disease.
Tissue-resident memory CD8+ T cells (TRM) are localized in non-lymphoid tissues throughout the body where they mediate long-lived protective immunity at common sites of pathogen exposure. As the signals controlling TRM differentiation are uncovered, it is becoming apparent that the dynamic activities of numerous transcription factors are intricately involved in TRM formation. Here, we highlight known transcriptional regulators of TRM differentiation and discuss how understanding the transcriptional programming of CD8+ T cell residency in non-lymphoid tissues can be leveraged to prevent or treat disease.
Cytotoxic CD8
T cells recognize and eliminate infected or cancerous cells. A subset of CD8
memory T cells called tissue-resident memory T cells (T
) resides in peripheral tissues, monitors the ...periphery for pathogen invasion, and offers a rapid and potent first line of defense at potential sites of re-infection. T
cells are found in almost all tissues and are transcriptionally and epigenetically distinct from circulating memory populations, which shows their ability to acclimate to the tissue environment to allow for long-term survival. Recent work and the broader availability of single-cell profiling have highlighted T
heterogeneity among different tissues, as well as identified specialized subsets within individual tissues, that are time and infection dependent. T
cell phenotypic and transcriptional heterogeneity has implications for understanding T
function and longevity. This review aims to summarize and discuss the latest findings on CD8
T
heterogeneity using single-cell molecular profiling and explore the potential implications for immune protection and the design of immune therapies.
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