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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’.

On 23–26 September 2024, the second ImmunOctoberfest conference took place in Raitenhaslach, Germany, and brought together scientists from all over the world to catch up on recent advances in ‘Bridging Innovation and Translation in T cell Immunotherapy’.

In this Viewpoint article, Nature Reviews Immunology invites 18 experts to discuss the nature of T cell exhaustion. How should T cell exhaustion be defined and what are the developmental relationships between exhausted T cell subsets? The contributors share their thoughts on key recent developments in the field.

Lymphatic endothelial cells (LECs) can cross-present antigen to naïve CD8⁺ T cells, but the significance of this interaction was unclear. Here the authors show that LECs directly induce CD8⁺ T cell differentiation with memory-like phenotypes, migration patterns and transcriptome, which can later be recalled to promote effector immunity and protection from Listeria infection.

Here the authors show that dihydroorotate dehydrogenase in the de novo pyrimidine synthesis pathway functions as a cell fate checkpoint that can be targeted to specifically diminish the number and function of effector T cells without affecting the memory T cell pool and response to infection.

How gut microbiota affect systemic responses to viral infection is still unclear. Here the authors use LCMV mouse infection model to show that a low complexity 12-strains community but not germ-free condition potentiates anti-viral immunity against LCMV beyond that of specific pathogen-free mice, but also aggravates LCMV-induced diseases.

T cell exhaustion was thought to be strictly associated only with chronic infections and tumours, but it turns out that acute infections also generate a subset of precursor T cells with exhaustion-like phenotypes.

During chronic infection, pathogen-specific CD8⁺ T cells are thought to terminally differentiate into exhausted cells. However, Zehn and colleagues show that T cells with memory-like properties are generated during such infections.

This paper reports the observation that T-cell expansion after initial activation occurs irrespective of TCR affinity. Low-affinity cells generate functional effector and memory responses; however, their expansion ceases earlier, resulting in an overall decreased total number of low-affinity cells compared to their high-affinity counterparts.

Klein and colleagues show that the lysosomal cysteine protease cathepsin L shapes the diversity and optimizes the fitness of clones that enter the CD4⁺ T cell repertoire.

Single-cell RNA-seq offers the opportunity to improve efficacy of T-cell based immunotherapy. Here the authors develop a plate-based method for cytotoxic T cell profiling. It captures a higher number of transcripts and detects gene with increased dynamic range in comparison to droplet-based methods.

The strength and duration of interleukin-2 (IL-2) signals is known to regulate T cell memory. Here the authors show that T cell receptor signalling strength controls the requirement for IL-2 signals to form CD8⁺ T cell memory with high functional activity and a wide range of genes with open chromatin regions.

Lo and colleagues provide evidence for the TCR kinetic proofreading model by LAT Gly135Asp alteration to reveal functional consequences of altered kinetics in TCR activation in thymic selection and mature T-cell responses.

Chronic viral infections and malignant tumours are associated with the development of T cells that have an 'exhausted' phenotype and that are thought to be severely functionally impaired. In this Opinion article, the authors propose that the exhausted phenotype is actually a functional adaptation to cause minimal tissue damage while still mediating a critical level of pathogen control.

NK cell tolerance to self-MHCI levels is calibrated during their development. Here the authors show that this tolerance is overcome by an inflammatory environment and that NLRC5 protects T cells from NK cell-mediated elimination by maintaining high MHCI expression.

A liver-intrinsic mechanism is presented that suppresses effective anti-hepatitis virus B responses in mice and humans by rendering virus-specific CD8 T cells refractory to activation causing loss of effector functions.

Chronic antigen exposure promotes terminal exhaustion of T cells. Here the authors show a role for TCR stimulation in preserving progenitor exhausted T cells and highlight their TCR-dependent self-renewal during antitumor responses.

For decades, beta-blockers have been used widely to treat cardiovascular diseases. Surprisingly, new data show how these inhibitors can also improve immunotherapy against tumors and chronic infections.

Through iterative cycles of viral challenge and rechallenge over ten years, mouse T cells are demonstrated to have essentially infinite potential for population expansion and longevity without malignant transformation or loss of functional competence.

In contrast with the classical dogma that the pathways generating either memory or ‘exhausted’ T cells are strictly segregated, data now identify a clonally distinct hybrid memory T cell subpopulation with an exhausted phenotype.

Zehn and colleagues review the cellular fates and precursor trajectories that allow antigen-specific CD8⁺ T cells to persist in the face of chronic infection and cancer.

Tumour-derived prostaglandin E₂, signaling through its receptors EP₂ and EP₄, is shown to restrain the responses of tumour-infiltrating stem-like TCF1⁺CD8⁺ T lymphocytes, and modulation of T cell EP₂ and EP₄ can restore anticancer immunity.

Waning immunity to SARS-CoV-2 is of concern. Here the authors follow spike- and nucleocapsid specific immunity in convalescent individuals for 9 months observing a decline in antibody levels but persisting T cell response. Vaccination approximately 11 months after infection boosts antibody and T cell immunity.

CD62L⁺ precursors of exhausted T cells retain long-term proliferative potential, multipotency and repopulation capacity, and the transcription factor MYB is essential for the development and function of this population of cells.

Liver resident CD8 T cells have an essential role in immunopathology in a mouse model of nonalcoholic steatohepatitis, by becoming auto-aggressive following sequential transcriptional and metabolic activation steps .

TGFβ secretion in the tumor microenvironment inhibits T cell-mediated anti-tumor immune responses. Here the authors show that a mutation predisposing to autoimmune diseases confers T cells resistance to TGFβ inhibitory action and could be exploited to engineer immunotherapies for TGFβ secreting tumors.

Virus-specific CD8⁺T cells lose effector function over the course of chronic infection, a process called ‘exhaustion’, but the fate of these cells after treatment-induced antigen elimination is unknown. Here the authors show that exhausted cells persist in patients even after direct-acting antiviral therapy removes antigen exposure, and that these cells are responsive on re-exposure to antigen.

Tolerance to self is engendered by multiple mechanisms. Lymph node stromal cells are now found to contribute to self-tolerance by their endogenous expression of peripheral tissue antigens.

TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infections.

Scellnetor is a single-cell network enrichment method that can unravel connected molecular interaction networks to explain the progression and differentiation of developmental trajectories on a systems biology level.

In this Review, the authors analyze functional and dysfunctional T cell features to make sense of cancer immunotherapy efficacy and how to improve it.

Autoreactive T cells are subject to continuous antigenic stimulation yet sustain their autoreactive functionality. Youngblood and colleagues examine type 1 diabetes systems to show that a pool of autoreactive CD8⁺ T cells exhibits a stem cell–like signature that facilitates their durable activity.

Recent studies have revealed a specialized population of ‘exhausted’ CD8⁺ T cells that expands on immune checkpoint blockade therapy for cancer and may explain how T cell responses are maintained in chronic conditions. Here, the authors describe their phenotypic, developmental and functional characteristics and why they should be harnessed for successful immunotherapy.