T cell exhaustion is a progressive loss of effector function due to prolonged antigen stimulation, characteristic of chronic infections and cancer. In addition to continuous antigen stimulation, antigen presenting cells and cytokines present in the microenvironment can also contribute to this exhausted phenotype.

Exhausted T cells typically express co-inhibitory receptors such as PD-1, Tim-3 and CTLA-4, and the reversal of T cell exhaustion by blocking these co-inhibitory receptors has received remarkable attention in the field of immunotherapy and tumor regression. However, these receptors are also pivotal for controlling the magnitude of normal T cell responses, to restore immune homeostasis and to control autoimmunity. Therefore, how can we determine whether blocking the signals transmitted through these co-inhibitory receptors is helpful or harmful to the body?

This Research Topic covers these points, discussing the importance of T cell exhaustion during physiologic versus pathological processes, covering articles from basic research to cancer treatment investigating (i) the transcriptional program executed during T cell exhaustion compared to other T cell states and (iii) the potential benefit in using combination therapies to reverse T cell exhaustion. We welcome the submission of Reviews, Mini-Reviews and Original Research articles covering the following topics:

1. The concept of T cell exhaustion and its associated mechanisms.
2. Exhaustion as a physiologic process to maintain homeostasis – bringing an end to regular immune responses, prevention of tissue damage and autoimmunity.
3. When exhaustion becomes an issue – autoimmunity/disease and anti-viral/anti-tumor responses.
4. The contribution of the tumor microenvironment to the induction / maintenance of T cell exhaustion including studies on APCs presenting antigen and expressing PD-L1; roles for B cells; DCs and/or macrophages.
5. Reversal of exhaustion – implications for immunotherapy, combination therapies and new strategies.

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Frontiers in Immunology

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