Precursors of exhausted T cells are preemptively formed in acute infection.

T cell exhaustion limits effector T cell function in chronic infection and tumors. The development of these hypofunctional T cells and of their precursors was considered to require stimulatory conditions met only upon persisting exposure to antigen and inflammation. In sharp contrast, we found similar T cell populations in the early phase of acute infections.

Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy.

Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy.

Chronic viral infection alters PD-1 locus subnuclear localization in cytotoxic CD8 T cells.

During chronic infection, virus-specific CD8 cytotoxic T lymphocytes (CTLs) progressively lose their ability to mount effective antiviral responses. This "exhaustion" is coupled to persistent upregulation of inhibitory receptor programmed death-1 (PD-1) (Pdcd1)-key in suppressing antiviral CTL responses. Here, we investigate allelic Pdcd1 subnuclear localization and transcription during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection in mice.

Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan.

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.

Cellular and molecular waypoints along the path of T cell exhaustion.

Thirty years of foundational research investigating molecular and cellular mechanisms promoting T cell exhaustion are now enabling rational design of T cell-based therapies for the treatment of chronic infections and cancer. Once described as a static cell fate, it is now well appreciated that the developmental path toward exhaustion is composed of a heterogeneous pool of cells with varying degrees of effector potential that ultimately converge on a terminally differentiated state. Recent description of the developmental stages along the differentiation trajectory of T cell exhaustion has provided insight into past immunotherapeutic success and future opportunities.

T cell TET2 disruption cuts the breaks on antitumor CAR T cell therapy.

Functional persistence of chimeric antigen receptor (CAR) T cells is required for sustaining an antitumor response. Recently, Jain et al. revealed that disruption of TET2 in CAR T cells resulted in antigen-independent CAR T cell hyperproliferation that enhanced tumor control in mice, highlighting the potential of epigenetic strategies to improve T cell-based cancer immunotherapy.

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’.

Improving antitumor T cells.

Disrupting cell cycle regulators can overcome anticancer T cell dysfunction.

Mechanisms of T cell exhaustion guiding next-generation immunotherapy.

The functional decline in T cells during their chronic stimulation, commonly referred to as T cell exhaustion, is a major limitation for current immunotherapy approaches. As modern medicine embraces therapeutic approaches that exploit the immuno-oncology interface, a primary question is how is T cell function maintained over time in scenarios of prolonged tumor burden. Deciphering the molecular mechanisms of T cell exhaustion is now enabling the field to begin using cardinal features of T cell differentiation to develop biomarkers that can delineate responders from nonresponders prior to treatment with T cell-based therapeutics.

Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation.

The immune system undergoes a progressive functional remodeling with age. Understanding how age bias shapes antitumor immunity is essential in designing effective immunotherapies, especially for pediatric patients. Here, we explore antitumor CD8 T cell responses generated in young (prepubescent) and adult (presenescent) mice.

CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia.

CD19-CAR T cell therapy has evolved into the standard of care for relapsed/refractory B cell acute lymphoblastic leukemia (ALL); however, limited persistence of the CAR T cells enables tumor relapse for many patients. To gain a deeper understanding of the molecular characteristics associated with CAR T cell differentiation, we performed longitudinal genome-wide DNA methylation profiling of CD8 CD19-CAR T cells post-infusion in ALL patients. We report that CAR T cells undergo a rapid and broad erasure of repressive DNA methylation reprograms at effector-associated genes.

Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity.

Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined.

Proinflammatory cytokines promote TET2-mediated DNA demethylation during CD8 T cell effector differentiation.

To gain insight into the signaling determinants of effector-associated DNA methylation programming among CD8 T cells, we explore the role of interleukin (IL)-12 in the imprinting of IFNg expression during CD8 T cell priming. We observe that anti-CD3/CD28-mediated stimulation of human naive CD8 T cells is not sufficient to induce substantial demethylation of the IFNg promoter. However, anti-CD3/CD28 stimulation in the presence of the inflammatory cytokine, IL-12, results in stable demethylation of the IFNg locus that is commensurate with IFNg expression.

BATF targets T cell exhaustion for termination.

New reports glean further insight into the role of the transcription factor BATF in pivoting the differentiation of CD8 T cells away from undergoing T cell exhaustion and facilitating transition of these cells into potent effectors.

CAR T cells need a pitstop to win the race.

Prolonged TCR-driven stimulation can induce a dysfunctional T cell state, broadly described as T cell exhaustion, limiting the clinical potential of chimeric antigen receptor (CAR) T cells. Recent findings in Science indicate that early cessation of CAR T cell tonic signaling can prevent stabilization of exhaustion-associated epigenetic programs, enabling a prolonged anti-tumor response.

Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL.

Chimeric antigen receptor (CAR)-T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires T-cell factor 1 (TCF-1), a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B-cell acute lymphoblastic leukemia (ALL; B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR-T-cell expansion and memory-like cell formation.

Epigenetic regulation of T cell adaptive immunity.

The conceptualization of adaptive immunity, founded on the observation of immunological memory, has served as the basis for modern vaccination and immunotherapy approaches. This fundamental concept has allowed immunologists to explore mechanisms that enable humoral and cellular lymphocytes to tailor immune response functions to a wide array of environmental insults and remain poised for future pathogenic encounters. Until recently, for T cells it has remained unclear how memory differentiation acquires and sustains a gene expression program that grants a cell with a capacity for a heightened recall response.

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand.

Stringent nonpharmaceutical interventions (NPIs) such as lockdowns and border closures are not currently recommended for pandemic influenza control. New Zealand used these NPIs to eliminate coronavirus disease 2019 during its first wave. Using multiple surveillance systems, we observed a parallel and unprecedented reduction of influenza and other respiratory viral infections in 2020.

Impact of the COVID-19 nonpharmaceutical interventions on influenza and other respiratory viral infections in New Zealand.

Stringent nonpharmaceutical interventions (NPIs) such as lockdowns and border closures are not currently recommended for pandemic influenza control. New Zealand used these NPIs to eliminate coronavirus disease 2019 during its first wave. Using multiple surveillance systems, we observed a parallel and unprecedented reduction of influenza and other respiratory viral infections in 2020.

Rewriting History: Epigenetic Reprogramming of CD8 T Cell Differentiation to Enhance Immunotherapy.

The full potential of T cell-based immunotherapies remains limited by a variety of T cell extrinsic and intrinsic immunosuppressive mechanisms that can become imprinted to stably reduce the antitumor ability of T cells. Here, we discuss recent insights into memory CD8 T cell differentiation and exhaustion and the association of these differentiation states with clinical outcomes during immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapeutic modalities. We consider the barriers limiting immunotherapy with a focus on epigenetic regulation impeding efficacy of adoptively transferred T cells and other approaches that augment T cell responses such as immune checkpoint blockade.

Beta cell-specific CD8 T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes.

The pool of beta cell-specific CD8 T cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell 'multipotency index' and found that beta cell-specific CD8 T cells retained a stem-like epigenetic multipotency score. Single-cell assay for transposase-accessible chromatin using sequencing confirmed the coexistence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8 T cells.

PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells.

In vivo persistence of chimeric antigen receptor (CAR)-modified T cells correlates with therapeutic efficacy, yet CAR-specific factors that support persistence are not well resolved. Using a CD33-specific CAR in an acute myeloid leukemia (AML) model, we show how CAR expression alters T cell differentiation in a ligand independent manner. Ex vivo expanded CAR-T cells demonstrated decreased naïve and stem memory populations and increased effector subsets relative to vector-transduced control cells.

Epigenetic Maintenance of Acquired Gene Expression Programs during Memory CD8 T Cell Homeostasis.

Memory CD8 T cells have a unique ability to provide lifelong immunity against pathogens containing their cognate epitope. Because of their ability to provide lifelong protection, the generation of memory T cells is now a major focus for current vaccination or adoptive cell therapy approaches to treat chronic viral infections and cancer. It is now clear that maintenance of memory CD8 T cells occurs through a process of antigen-independent homeostatic proliferation, which is regulated in part by the gamma chain cytokines IL-7 and IL-15.