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Immune responses in tissues are constrained by the physiological properties of the tissue involved. Tissue-resident memory T cells (T RM cells) are a recently discovered lineage of T cells specialized for life and function within tissues. Emerging evidence has shown that T RM cells have a special role in the control of solid tumors. A high frequency of T RM cells in tumors correlates with favorable disease progression in patients with cancer, and studies of mice have shown that T RM cells are necessary for optimal immunological control of solid tumors. Here we describe what defines T RM cells as a separate lineage and how these cells are generated. Furthermore, we discuss the properties that allow T RM cells to operate in normal and transformed tissues, as well as implications for the treatment of patients with cancer. Tissue-resident memory T cells provide immunological protection in peripheral tissues. Amsen et al . discuss the role of these cells in the context of anti-tumor immunity.

Specialized subpopulations of CD4 + T cells survey major histocompatibility complex class II–peptide complexes to control phagosomal infections, help B cells, regulate tissue homeostasis and repair or perform immune regulation. Memory CD4 + T cells are positioned throughout the body and not only protect the tissues from reinfection and cancer, but also participate in allergy, autoimmunity, graft rejection and chronic inflammation. Here we provide updates on our understanding of the longevity, functional heterogeneity, differentiation, plasticity, migration and human immunodeficiency virus reservoirs as well as key technological advances that are facilitating the characterization of memory CD4 + T cell biology. In this Review, Künzli and Masopust provide updates on our understanding of the biology of memory CD4 + T cells as well as key technological advances that facilitate their characterization.

Exhausted CD8 + T (T ex ) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T eff ) or memory (T mem ) CD8 + T cells. T ex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T ex cells are a distinct immune subset, with a unique chromatin landscape compared with T eff and T mem cells. However, the mechanisms that govern the transcriptional and epigenetic development of T ex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T ex cells in mice. TOX is largely dispensable for the formation of T eff and T mem cells, but it is critical for exhaustion: in the absence of TOX, T ex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T ex cells. Robust expression of TOX therefore results in commitment to T ex cells by translating persistent stimulation into a distinct T ex cell transcriptional and epigenetic developmental program. The transcription factor TOX is a central regulator of the transcriptional and epigenetic development of exhausted T cells.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, we used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave. These studies revealed heightened spike-specific responses during infection of vaccinated compared to unvaccinated individuals. Spike-specific cluster of differentiation (CD)4 T cells and plasmablasts expanded and CD8 T cells were robustly activated during the first week. In contrast, memory B cell activation, neutralizing antibody production and primary responses to nonspike antigens occurred during the second week. Collectively, these data demonstrate the functionality of vaccine-primed immune memory and highlight memory T cells as rapid responders during SARS-CoV-2 infection. Wherry and colleagues define the kinetics of vaccine-primed recall immune responses during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection, highlighting rapid activation of memory T cells and broadly enhanced immune responses in previously vaccinated individuals.

SARS-CoV-2 spike mRNA vaccines 1 – 3 mediate protection from severe disease as early as ten days after prime vaccination 3 , when neutralizing antibodies are hardly detectable 4 – 6 . Vaccine-induced CD8 + T cells may therefore be the main mediators of protection at this early stage 7 , 8 . The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8 + T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4 + T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8 + T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8 + T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination. Longitudinal analyses of SARS-CoV-2 mRNA vaccine-elicited epitope-specific CD8 + T cell responses shows that CD8 + T cells are rapidly induced after prime vaccination and stably maintained after boost vaccination.

Emerging data indicate that SARS-CoV-2-specific CD8 + T cells targeting different viral proteins are detectable in up to 70% of convalescent individuals 1 – 5 . However, very little information is currently available about the abundance, phenotype, functional capacity and fate of pre-existing and induced SARS-CoV-2-specific CD8 + T cell responses during the natural course of SARS-CoV-2 infection. Here, we define a set of optimal and dominant SARS-CoV-2-specific CD8 + T cell epitopes. We also perform a high-resolution ex vivo analysis of pre-existing and induced SARS-CoV-2-specific CD8 + T cells, applying peptide-loaded major histocompatibility complex class I (pMHCI) tetramer technology. We observe rapid induction, prolonged contraction and emergence of heterogeneous and functionally competent cross-reactive and induced memory CD8 + T cell responses in cross-sectionally analyzed individuals with mild disease following SARS-CoV-2 infection and three individuals longitudinally assessed for their T cells pre- and post-SARS-CoV-2 infection. SARS-CoV-2-specific memory CD8 + T cells exhibited functional characteristics comparable to influenza-specific CD8 + T cells and were detectable in SARS-CoV-2 convalescent individuals who were seronegative for anti-SARS-CoV-2 antibodies targeting spike (S) and nucleoprotein (N). These results define cross-reactive and induced SARS-CoV-2-specific CD8 + T cell responses as potentially important determinants of immune protection in mild SARS-CoV-2 infection. Functionally competent memory CD8 + T cells specific for different viral epitopes are induced by SARS-CoV-2 infection and can be detected in the absence of virus-specific antibodies.

Tissue-resident memory CD8+ T (CD8 T RM ) cells are an essential component of protective immune responses at barrier tissues, including the female genital tract. However, the mechanisms that lead to the initiation of CD8 T RM -mediated protective immunity after viral infection are unclear. Here we report that CD8 T RM cells established by ‘prime and pull’ method confer protection against genital HSV-2 infection, and that IFN-γ produced by CD8 T RM cells is required for this protection. Furthermore, we find that CD8 T RM -cell restimulation depends on a population of CD301b + antigen-presenting cells (APC) in the lamina propria. Elimination of MHC class I on CD301b + dendritic cells abrogates protective immunity, suggesting the requirement for cognate antigen presentation to CD8 T RM cells by CD301b + dendritic cells. These results define the requirements for CD8 T RM cells in protection against genital HSV-2 infection and identify the population of APC that are responsible for activating these cells. Tissue-resident memory T cells are needed for optimal antiviral immunity at mucosal surfaces. Here the authors provide a mechanism for this protection, showing that vaginal CD301b+ DC-dependent IFN-γ production by CD8+ tissue-resident memory T cells, not circulating T cells, is central to HSV-2 resistance.

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential 1 – 4 . This process, known as T cell exhaustion or dysfunction 1 , is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1) 5 – 8 . The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood 9 – 12 . Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein 13 – 15 . TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1 + self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology. TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infections.

Immune surveillance against pathogens and tumours in the central nervous system is thought to be limited owing to the lack of lymphatic drainage. However, the characterization of the meningeal lymphatic network has shed light on previously unappreciated ways that an immune response can be elicited to antigens that are expressed in the brain 1 – 3 . Despite progress in our understanding of the development and structure of the meningeal lymphatic system, the contribution of this network in evoking a protective antigen-specific immune response in the brain remains unclear. Here, using a mouse model of glioblastoma, we show that the meningeal lymphatic vasculature can be manipulated to mount better immune responses against brain tumours. The immunity that is mediated by CD8 T cells to the glioblastoma antigen is very limited when the tumour is confined to the central nervous system, resulting in uncontrolled tumour growth. However, ectopic expression of vascular endothelial growth factor C (VEGF-C) promotes enhanced priming of CD8 T cells in the draining deep cervical lymph nodes, migration of CD8 T cells into the tumour, rapid clearance of the glioblastoma and a long-lasting antitumour memory response. Furthermore, transfection of an mRNA construct that expresses VEGF-C works synergistically with checkpoint blockade therapy to eradicate existing glioblastoma. These results reveal the capacity of VEGF-C to promote immune surveillance of tumours, and suggest a new therapeutic approach to treat brain tumours. In a mouse model of glioblastoma, treatment with VEGF-C increases lymphatic drainage in the central nervous system and improves the immune response, suggesting that modulating meningeal lymphatics could enhance checkpoint inhibitor therapy.