Trends in Immunology
ReviewMolecular Dissection of CD8+ T-Cell Dysfunction
Section snippets
T-Cell Dysfunction
In chronic disease settings, such as in chronic viral infections and cancer, effector CD8+ T cells progressively acquire an ‘exhausted’ or dysfunctional T-cell state characterized by variable deficits in their effector functions, including cytotoxicity and the production of proinflammatory cytokines [interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ)] [1] (Figure 1A). Importantly, dysfunctional CD8+ T cells are not completely inert as it has been shown that they can
Molecular Signatures of T-Cell Dysfunction
Several gene signatures based on analyses of populations of dysfunctional CD8+ T cells from cancer and chronic viral infections have been published 9, 21, 22, 23, 24, 25. These signatures have shown that there is great similarity between virus- and cancer-associated CD8+ T-cell dysfunction and have greatly advanced our understanding of factors that contribute to dysfunctional phenotype. Comparisons of the gene expression profiles of functional versus dysfunctional virus-specific CD8+ T cells
Gene Modules for T-Cell Dysfunction and Activation
While the dysfunction signatures discussed earlier have been useful in identifying factors that contribute to T-cell dysfunction, it was noted early on that these signatures highly overlap with signatures of healthy T-cell activation (reviewed in [29]). For example, co-inhibitory receptors (e.g., PD-1, Tim-3, CTLA-4) and effector molecules (e.g., GZMC, IFN-γ) present in the dysfunction signatures have been shown to be associated with healthy T-cell activation. This overlap between the
Heterogeneity of CD8+ T-Cell States within Tumor
The discovery of refined gene modules for T-cell dysfunction, activation/dysfunction, and activation raises the question of how these modules are expressed in individual CD8+ T cells and how this relates to their functional phenotype (Figure 1B). For example, do the dysfunctional CD8+ T cells previously defined based on surface expression of co-inhibitory receptors uniformly express the activation/dysfunction and dysfunction modules or are there subpopulations that express these modules to
Transcription Factors
In addition to Gata3 [24], several other transcription factors have been shown to play a role in promoting CD8+ T-cell dysfunction. The leucine zipper-containing transcription factor Maf was reported to be upregulated in dysfunctional CD8+ TILs in murine melanoma tumors and in TILs from melanoma patients when compared with naïve and effector CD8+ T cells [9]. Loss of Maf resulted in better tumor control while overexpression resulted in dampened TIL accumulation and antitumor activity. Martinez
Implications for Therapy
Immunotherapies, such as co-inhibitory receptor blockade and adoptive T-cell transfer, are transforming the treatment for advanced cancer [50]. Understanding how these therapies work and finding ways to improve them is an active area of research 51, 52, 53, 54, 55. Technological advances such as in-depth genomic analyses will be instrumental in this regard. Indeed, such analyses have shown that CTLA-4 and PD-1 blockade therapies achieve efficacy through distinct mechanisms [56]. Moreover,
Concluding Remarks and Future Perspectives
Single-cell analysis has the potential to identify new and more refined gene modules in CD8+ T cells. It will be important to discern transient from more stable states, potentially with epigenetic analysis coupled with perturbations (see Outstanding Questions). Testing whether the different transcriptional populations identified by single-cell transcriptomics are distinct in cytotoxicity, cytokine secretion, proliferative capacity, and T-cell receptor expression will resolve their functional
Acknowledgments
A.C.A. acknowledges support from the National Institutes of Health (R01CA187975 and P01AI073748).
Glossary
- Gene module
- a set of genes that have similar expression profiles across conditions tested. Gene modules may include hundreds or even thousands of genes. Unlike a gene signature, a module does not necessarily define a specific cell state. For example, a dysfunction/activation module for CD8+ T cells consists of genes that are upregulated in both the dysfunction and activation states.
- Gene signature
- a set of genes that defines a specific cell state. Typically, gene signatures include tens to
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2021, European Journal of PharmacologyCitation Excerpt :MT1 and MT2 play a key role in the proliferation and activation of CD8+ T lymphocytes (Chen et al., 2016). It has been revealed that the dysfunctional CD8+ T lymphocytes show loss of both MT1 and MT2 (Wang et al., 2017). Downregulation of MT1/MT2 in Jurkat cells is associated with a remarkable reduction in the production of IL-2 (Reppert, 1997).