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CD4 + T cells are typically considered as 'helper' or 'regulatory' populations that support and orchestrate the responses of other lymphocytes. However, they can also develop potent granzyme (Gzm)-mediated cytotoxic activity and CD4 + cytotoxic T cells (CTLs) have been amply documented both in humans and in mice, particularly in the context of human chronic infection and cancer. Despite the established description of CD4 + CTLs, as well as of the critical cytotoxic activity they exert against MHC class II-expressing targets, their developmental and memory maintenance requirements remain elusive. This is at least in part owing to the lack of a murine experimental system where CD4 + CTLs are stably induced. Here, we show that viral and bacterial vectors encoding the same epitope induce distinct CD4 + CTL responses in challenged mice, all of which are nevertheless transient in nature and lack recall properties. Consistent with prior reports, CD4 + CTL differentiation is accompanied by loss of TCF-1 expression, a transcription factor considered essential for memory T cell survival. Using genetic ablation of Tcf7 , which encodes TCF-1, at the time of CD4 + T cell activation, we further show that, contrary to observations in CD8 + T cells, continued expression of TCF-1 is not required for CD4 + T cell memory survival. Whilst Tcf7 -deficient CD4 + T cells persisted normally following retroviral infection, the CD4 + CTL subset still declined, precluding conclusive determination of the requirement for TCF-1 for murine CD4 + CTL survival. Using xenotransplantation of human CD4 + T cells into murine recipients, we demonstrate that human CD4 + CTLs develop and persist in the same experimental conditions where murine CD4 + CTLs fail to persist. These observations uncover a species-specific defect in murine CD4 + CTL persistence with implications for their use as a model system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hofland, Danelli, Cornish, Donnarumma, Hunt, de Carvalho and Kassiotis.)

During chronic antigen exposure, a subset of exhausted CD8 + T cells differentiate into stem cell-like or progenitor-like T cells expressing both transcription factor Tcf-1 (T cell factor-1) and co-inhibitory receptor PD-1. These Tcf-1 + stem-like or progenitor exhausted T cells represent the key target for immunotherapies. Deeper understanding of the biology of Tcf-1 + PD-1 + CD8 + T cells will lead to rational design of future immunotherapies. Here, we summarize recent findings about the migratory and resident behavior of Tcf-1 + T cells. Specifically, we will focus on TGF-β-dependent lymphoid tissue residency program of Tcf-1 + T cells, which may represent a key to understanding the differentiation and maintenance of Tcf-1 + stem-like CD8 + T cells during persistent antigen stimulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ma and Zhang.)

Exhausted CD8 + T (Tex) cells are a distinct cell population that arise during persistent antigen exposure in the context of chronic infections and cancers. Although characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression and distinct transcriptional and epigenetic programs, Tex cells are heterogeneous. Among these, a self-renewing TCF-1 +  Tex population, having unique characteristics and the ability to respond to immune-checkpoint blockade, gives rise to TCF-1 - terminally Tex cells. These TCF-1 +  cells have stem cell-like properties similar to memory T cell populations, but the signals that regulate the developmental pathways and relationships among exhausted cell populations are still unclear. Here, we review our current understanding of Tex cell biology, and discuss some less appreciated molecules and pathways affecting T cell exhaustion. We highlight two co-stimulatory receptors, CD226 and CD137, and their role in inducing or restraining T cell exhaustion, as well as signaling pathways that may be amenable to pharmacological inhibition with a focus on Phosphoinositide-3 Kinase and IL-2 partial agonists. Finally, we discuss novel methods that may increase TCF-1 + populations and therefore improve immunotherapy responsiveness. Understanding features of and pathways to exhaustion has important implications for the success of immunotherapy, including checkpoint blockade and adoptive T-cell transfer therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pichler, Cannons and Schwartzberg.)

The transcription factor TCF-1 (encoded by Tcf7 ) plays critical roles in several lineages of hematopoietic cells. In this study, we examined the molecular basis for Tcf7 regulation in T cells, innate lymphoid cells, and migratory conventional dendritic cells that we find express Tcf7 . We identified a 1 kb regulatory element crucial for the initiation of Tcf7 expression in T cells and innate lymphoid cells, but dispensable for Tcf7 expression in Tcf7 -expressing dendritic cells. Within this region, we identified a Notch binding site important for the initiation of Tcf7 expression in T cells but not in innate lymphoid cells. Our work establishes that the same regulatory element is used by distinct transcriptional controllers to initiate Tcf7 expression in T cells and ILCs., (Copyright © 2020 Harly, Kenney, Wang, Ding, Zhao, Awasthi and Bhandoola.)

Tissue-resident memory CD8 + T (T RM ) cells that develop in the epithelia at portals of pathogen entry are important for improved protection against re-infection. CD8 + T RM cells within the skin and the small intestine are long-lived and maintained independently of circulating memory CD8 + T cells. In contrast to CD8 + T RM cells at these sites, CD8 + T RM cells that arise after influenza virus infection within the lungs display high turnover and require constant recruitment from the circulating memory pool for long-term persistence. The distinct characteristics of CD8 + T RM cell maintenance within the lungs may suggest a unique program of transcriptional regulation of influenza-specific CD8 + T RM cells. We have previously demonstrated that the transcription factors Hobit and Blimp-1 are essential for the formation of CD8 + T RM cells across several tissues, including skin, liver, kidneys, and the small intestine. Here, we addressed the roles of Hobit and Blimp-1 in CD8 + T RM cell differentiation in the lungs after influenza infection using mice deficient for these transcription factors. Hobit was not required for the formation of influenza-specific CD8 + T RM cells in the lungs. In contrast, Blimp-1 was essential for the differentiation of lung CD8 + T RM cells and inhibited the differentiation of central memory CD8 + T (T CM ) cells. We conclude that Blimp-1 rather than Hobit mediates the formation of CD8 + T RM cells in the lungs, potentially through control of the lineage choice between T CM and T RM cells during the differentiation of influenza-specific CD8 + T cells.