Dynamic landscapes and protective immunity coordinated by influenza-specific lung-resident memory CD8 T cells revealed by intravital imaging.

Lung-tissue-resident memory (T) CD8 T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How T cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung T cells before and after recall infection.

T cell dysfunction and therapeutic intervention in cancer.

Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells.

Antitumor progenitor exhausted CD8 T cells are sustained by TCR engagement.

The durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8 T cells (Tpex). Tpex serve as a resource for replenishing effector T cells and preserve their quantity through self-renewal. However, it is unknown how T cell receptor (TCR) engagement affects the self-renewal capacity of Tpex in settings of continued antigen exposure.

PGE limits effector expansion of tumour-infiltrating stem-like CD8 T cells.

Cancer-specific TCF1 stem-like CD8 T cells can drive protective anticancer immunity through expansion and effector cell differentiation; however, this response is dysfunctional in tumours. Current cancer immunotherapies can promote anticancer responses through TCF1 stem-like CD8 T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1CD8 T cell-mediated anticancer immunity.

Stat5a sobers up inTOXicated T cells.

Exhausted T cells are largely hampered by epigenetically enforced mechanisms that limit their effector potential. In this issue of Immunity, Beltra et al. found that Stat5 can alter these epigenetic profiles when T cells transition from the Tpex precursor stage into differentiated cells.

Responses of patients with cancer to mRNA vaccines depend on the time interval between vaccination and last treatment.

Background: Personalized mRNA vaccines are promising new therapeutic options for patients with cancer. Because mRNA vaccines are not yet approved for first-line therapy, the vaccines are presently applied to individuals that received prior therapies that can have immunocompromising effects. There is a need to address how prior treatments impact mRNA vaccine outcomes.

A single-amino acid substitution in the adaptor LAT accelerates TCR proofreading kinetics and alters T-cell selection, maintenance and function.

Mature T cells must discriminate between brief interactions with self-peptides and prolonged binding to agonists. The kinetic proofreading model posits that certain T-cell antigen receptor signaling nodes serve as molecular timers to facilitate such discrimination. However, the physiological significance of this regulatory mechanism and the pathological consequences of disrupting it are unknown.

The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1 CD8 T cells in chronic viral infection.

T cell factor 1 (Tcf-1) expressing CD8 T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8 T cells (CD8SL) remain poorly defined. Studying CD8 T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8SL as well as for virus control.

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected.

Functional T cells are capable of supernumerary cell division and longevity.

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans. To provide immunity, transiently stimulated CD8 T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits.

Tapping the keg of discovery to advance T cell therapy.

Starting on 19 September 2022, the very first ImmunOctoberfest conference took place in Raitenhaslach, Germany, bringing together scientists from all over the world to discuss ‘bridging innovation and translation in T cell immunotherapy’.

Secondary infections rejuvenate the intestinal CD103 tissue-resident memory T cell pool.

Resident T lymphocytes (T) protect tissues during pathogen reexposure. Although T phenotype and restricted migratory pattern are established, we have a limited understanding of their response kinetics, stability, and turnover during reinfections. Such characterizations have been restricted by the absence of in vivo fate-mapping systems.

T cell receptor and IL-2 signaling strength control memory CD8 T cell functional fitness via chromatin remodeling.

Cognate antigen signal controls CD8 T cell priming, expansion size and effector versus memory cell fates, but it is not known if and how it modulates the functional features of memory CD8 T cells. Here we show that the strength of T cell receptor (TCR) signaling controls the requirement for interleukin-2 (IL-2) signals to form a pool of memory CD8 T cells that competitively re-expand upon secondary antigen encounter. Combining strong TCR and intact IL-2 signaling during priming synergistically induces genome-wide chromatin accessibility in regions targeting a wide breadth of biological processes, consistent with greater T cell functional fitness.

Type 1 conventional dendritic cells maintain and guide the differentiation of precursors of exhausted T cells in distinct cellular niches.

Reinvigoration of exhausted CD8 T (Tex) cells by checkpoint immunotherapy depends on the activation of precursors of exhausted T (Tpex) cells, but the local anatomical context of their maintenance, differentiation, and interplay with other cells is not well understood. Here, we identified transcriptionally distinct Tpex subpopulations, mapped their differentiation trajectories via transitory cellular states toward Tex cells, and localized these cell states to specific splenic niches. Conventional dendritic cells (cDCs) were critical for successful αPD-L1 therapy and were required to mediate viral control.

Dynamics of spike-and nucleocapsid specific immunity during long-term follow-up and vaccination of SARS-CoV-2 convalescents.

Anti-viral immunity continuously declines over time after SARS-CoV-2 infection. Here, we characterize the dynamics of anti-viral immunity during long-term follow-up and after BNT162b2 mRNA-vaccination in convalescents after asymptomatic or mild SARS-CoV-2 infection. Virus-specific and virus-neutralizing antibody titers rapidly declined in convalescents over 9 months after infection, whereas virus-specific cytokine-producing polyfunctional T cells persisted, among which IL-2-producing T cells correlated with virus-neutralizing antibody titers.

Mastering an exhausting marathon: how CD8 T cells fine-tune metabolic fitness.

A recent study by Gabriel et al. provides novel insight into the metabolic pathways that contribute to T cell differentiation in chronic infection. The researchers discovered that metabolic plasticity and the function of exhausted T cells is regulated via the TGF-β-mTOR signaling axis.

Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections.

Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection.

The role of exhaustion in CAR T cell therapy.

CAR T cell therapy successes are challenged by several mechanisms of resistance including the development of dysfunctional states such as exhaustion. The features of CAR T cell exhaustion, its role in limiting the efficacy of CAR T therapy in both liquid and solid malignancies, and potential strategies to overcome it are discussed.

Cervicovaginal Tissue Residence Confers a Distinct Differentiation Program upon Memory CD8 T Cells.

Tissue-resident memory CD8 T cells (CD8 T) are critical for maintaining barrier immunity. CD8 T have been mainly studied in the skin, lung and gut, with recent studies suggesting that the signals that control tissue residence and phenotype are highly tissue dependent. We examined the T cell compartment in healthy human cervicovaginal tissue (CVT) and found that most CD8 T cells were granzyme B and TCF-1 To address if this phenotype is driven by CVT tissue residence, we used a mouse model to control for environmental factors.

Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8+ T cells.

T cell receptor (TCR) stimulation leads to the expression of the transcription factor thymocyte selection-associated high-mobility group box (TOX). Prolonged TCR signaling, such as encountered during chronic infections or in tumors, leads to sustained TOX expression, which is required for the induction of a state of exhaustion or dysfunction. Although CD8+ memory T (Tmem) cells in mice typically do not express TOX at steady state, some human Tmem cells express TOX but appear fully functional.