Chronic infections promote the terminal differentiation (or "exhaustion") of T cells and are thought to preclude the formation of memory T cells. In contrast, we discovered a small subpopulation of virus-specific CD8(+) T cells that sustained the T cell response during chronic infections. These cells were defined by, and depended on, the expression of the transcription factor Tcf1. Transcriptome analysis revealed that this population shared key characteristics of central memory cells but lacked an effector signature. Unlike conventional memory cells, Tcf1-expressing T cells displayed hallmarks of an "exhausted" phenotype, including the expression of inhibitory receptors such as PD-1 and Lag-3. This population was crucial for the T cell expansion that occurred in response to inhibitory receptor blockade during chronic infection. These findings identify a memory-like T cell population that sustains T cell responses and is a prime target for therapeutic interventions to improve the immune response in chronic infections.

The contributors Christian U. Blank is a medical oncologist and principal investigator at the Netherlands Cancer Institute. He is Professor of Haematology/oncology at the university of Regensburg, Germany, and received an MBA degree from the university of Warwick, UK. His research interests include neoadjuvant immunotherapies, targeted and biological response modifiers, and prognostic markers for cancer immunotherapies. W. Nicholas Haining is a physician-scientist and vice-President for Discovery oncology and Immunology at Merck Research Laboratories. His former academic laboratory at the Dana-Farber Cancer Institute and the Broad Institute focused on understanding the transcriptional control of T cell exhaustion and on identifying regulators of the immune response to cancer in tumour and immune cells. Werner Held's laboratory has a long-standing interest in understanding the development, differentiation and function of natural killer cells and CD8 + T cells. Current work focuses on CD8 + T cell differentiation in response to acute and chronic infections as well as cancer. Patrick G. Hogan's research centres on mechanisms and regulation of cellular calcium signalling, the biology of the nuclear factor of activated T cells (NFAT) family of transcription factors and the transcriptional control of immune cell development and function. Axel Kallies is a professor at the University of Melbourne, Australia. His laboratory studies the molecular control of CD8 + cytotoxic T cell and regulatory T cell differentiation with a focus on populations residing in non-lymphoid tissue, including healthy tissues and tumours. The Kallies laboratory has developed and applied genetic and molecular approaches to this field, including novel gene reporters, metabolic techniques, transcriptional profiling, chromatin immunoprecipitation and accessible chromatin sequencing. Enrico Lugli's laboratory is focused on understanding the biological mechanisms at the basis of memory T cell responses and homeostasis in humans and how this information can be exploited to favour antitumour immune responses in patients with cancer. The group is specialized in single-cell technologies, in particular high-dimensional flow cytometry. Rachel C. Lynn is an associate director of research at Lyell Immunopharma. She received her PhD degree from the the university of Pennsylvania, where she developed multiple preclinical chimeric antigen receptor (CAR) T cell therapy platforms. During her postdoctoral work with Crystal mackall at Stanford university, she developed models to interrogate and strategies to mitigate CAR T cell exhaustion. At Lyell Immunopharma, her research group will continue to investigate optimal strategies for adoptive T cell therapy in cancer.

Following an infection, CD8+ T cells are activated and undergo a characteristic kinetic sequence of rapid expansion, subsequent contraction and formation of memory cells1–3. The pool of naïve T cell clones is diverse and contains cells bearing T cell antigen receptors (TCR) that differ in their affinity for the same antigen4,5. How these differences in affinity impact the function and the response kinetics of individual T cell clones was previously unknown. Here we show that during the in vivo response to microbial infection, even very weak TCR-ligand interactions are sufficient to activate naïve T cells, induce rapid initial proliferation and generate effector and memory cells. The strength of the TCR-ligand interaction critically impacts when expansion stops, when the cells exit lymphoid organs and when contraction begins, i.e. strongly stimulated T cells contract and exit lymphoid organs later than do weakly stimulated cells. Our data challenges the prevailing view that strong TCR ligation is a prerequisite for CD8+ T cell activation. Instead, very weak interactions are sufficient for activation, but strong TCR ligation is required to sustain T cell expansion. We propose that in response to microbial challenge, T cell clones with a broad range of avidities for foreign ligands are initially recruited, and that the pool of T cells subsequently matures in affinity due to the more prolonged expansion of high affinity T cell clones.

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