et al. Invest. PLoS Med. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. We now know that the exhaustion of such stem-like cells is, at least in some situations, reversible [12], contrasting with the long-held view that exhaustion would necessarily be irreversible [3,1921]. Nature Immunology Nature 439, 682687 (2006). His research focuses on the dissection of tumour-specific T cell responses in human cancer. 76, 829840 (2002). Biol. 203, 24612472 (2006). et al. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Immunology (Nat Immunol) There are, in fact, many parameters that help explain the elimination or non-elimination of the tumor by T cells, and each of these parameters can be linked to biomarkersas suggested by the concept of the cancer immunogram [84]. Zeng, M. et al. One major limitation is that, in general, exhausted T cells are said to be dysfunctional with a unique and preexistent idea of function in mindnamely, the function to eliminate the virus. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. Frontiers | Characterizing the Dysfunctional NK Cell: Assessing the Blackburn, S. D., Shin, H., Freeman, G. J. Continuous recruitment of nave T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. Acad. Kasprowicz, V. et al. Blood 96, 10211029 (2000). 12, 492499 (2011). E.J.W. E.J.W. The perspective presented in this paper opens up original and promising avenues for future research in at least 3 areas: Discussing the definition of exhaustion is not just a matter of words. Minimally, this forces us to recognize that PD-1 might be a necessary, although insufficient, marker of exhaustion and that exhaustion corresponds to a cluster of several markers rather than just 1 marker [54]. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Epigenetic signature of PD-1+TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. Yao, C. et al. Nat. Gastroenterology 134, 19271937 (2008). In reality, though, these 3 approaches often fail to overlap. et al. Immunol. Haining, W.N. Following the work of Zinkernagel and Ahmed, the concept of exhaustion has most of the time been applied to CD8 T cells, although it is also sometimes attributed to other immune cells (especially CD4 T cells) (e.g., [6]). Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors. The aim of cancer therapies based on immune checkpoint inhibitors is to target dysfunctional T cells in cancer by reversing their state of tolerance to the tumor [66,67]. 276, 125144 (2003). Top. 77, 49114927 (2003). Interleukin-10 determines viral clearance or persistence in vivo. J. Immunol. Expression of 'exhaustion' or 'immune checkpoint' markers in early HIV-1 infection is associated with clinical progression and is impacted by immune activation and the duration of infection. Natl. 203, 22232227 (2006). I thank the members of my laboratory and N. Haining for discussions. Miller, N.E., Bonczyk, J.R., Nakayama, Y. This constitutes a genuine functional characterization of exhaustion. Nat. Rev. are funded by National Institutes of Health grants AI109842, AI040127 and AI084167, and U01 DE028227. Because we propose that it is essential for immunologists to distinguish the 3 approaches and make explicit in each experimental or therapeutic context which approach(es) they have in mind, we will try to present as precisely as possible these 3 approaches. Thank you for visiting nature.com. 120, 40774090 (2011). In recent years, many have connected the literature on immunotherapies with the preexisting literature on immunological exhaustion and claimed that targeting dysfunctional T cells in cancer amounted to targeting exhausted T cells [41, 6870]. J. Virol. Infection of dendritic cells by lymphocytic choriomeningitis virus. J. Exp. is supported by a fellowship by the National Health and Medical Research Council of Australia. Recent studies have also highlighted an important role for the transcriptional regulator TOX in driving the epigenetic enforcement of exhaustion, but key questions remain about the potential to reverse the epigenetic programme of exhaustion and how this might affect the persistence of T cell populations. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. Science 348, 6268 (2015). Annu. Thus, the function of PD-1 is interpreted differently depending on where and when it has been studiedsometimes as a sign of exhaustion, sometimes not. Overall, exhaustion has classically been defined both by dysfunction (these T cells fail to do what effector T cells are expected to do) and by a double cause (high viral load and chronicity). Proc. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Consequently, misunderstanding the exhausted profile as an indiscriminate need for T-cell reinvigoration could lead to clinical disaster for the patient. Immune exhaustion occurs concomitantly with immune activation - PubMed 207, 21752186 (2010). has a patent licensing agreement on the PD1 pathway with Roche/Genentech. Mueller, S.N. Schietinger, A. et al. Immunol. Science 354, 11601165 (2016). PubMed Central Immunol., 16 December 2021 Sec. Invest. PubMed Velu, V. et al. Authors have called these cells dysfunctional because they compare their functions in the context of a high-dose persistent chronic viral infection with the functions of the same cells in the context of acute viral infection when the virus is cleared [1]. Blackburn, S.D. First, for the clinician, targeting exhausted T cells will have a very different meaning depending on whether what is targeted is the dysfunction itself, the underlying causes, or the markers of exhaustion (Fig 3). Fig 2 sums up the main controversies about exhaustion. Leone, A., Picker, L.J. USA 107, 1473314738 (2010). 81, 58825892 (2007). Frontiers | Colorectal Cancer-Associated Immune Exhaustion Involves T Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Natl. PubMed Central J. Exp. Keywords: HAVCR2, immune transcriptomics, NSCLC, TIM-3, immune cell exhaustion Go to: Introduction Lung cancer is the leading cause of cancer related deaths worldwide ( 1 ). Hannah Kaminski, The phenomenon of disease tolerance reflects the fact that, in terms of fitness, it is sometimes better to mitigate the impact of a source of damage rather than eliminate it. et al. Macian, F. et al. . Nature 443, 350354 (2006). Med. Sci. et al. Infect. Acad. This strategy could be perfectly reasonable, and we see much value in adopting it, because it would force everyone to be more specific and rigorous when talking about exhaustion. J. Clin. Presentation details. Cell. Kurtulus, S. et al. Her laboratory at Memorial Sloan Kettering Cancer Center studies the regulatory molecular and epigenetic mechanisms underlying T cell differentiation and dysfunction in the context of self-tolerance, autoimmunity and tumours. Sevilla, N., Kunz, S., McGavern, D. & Oldstone, M.B. Cell 176, 775789 (2019). At Lyell Immunopharma, her research group will continue to investigate optimal strategies for adoptive T cell therapy in cancer. Mary Philip is an assistant professor in the Department of Medicine, Division of Hematology and Oncology and Department of Pathology, Microbiology, and Immunology at Vanderbilt University Medical Center. The group is specialized in single-cell technologies, in particular high-dimensional flow cytometry. Cell 109, 719731 (2002). Angelosanto, J. M., Blackburn, S. D., Crawford, A. Clin. Sci. PLoS Pathog 17(9): & Oldstone, M.B. Clarifying the characteristics of cells defined as exhausted, and using a convergent strategy to define T-cell exhaustion could have major experimental and clinical consequences, including for viral infections such as the Coronavirus Disease 2019 (COVID-19). T cell stemness and dysfunction in tumors are triggered by a common mechanism. et al. J. Immunol. We investigated the relationship of these 2 phenotypes and frequency of regulatory T cells (Tregs) in controlled and uncontrolled chronic HIV-1 infection. Alfei, F. et al. 15, 808813 (2009). Sci. Nat. During her postdoctoral work with Crystal Mackall at Stanford University, she developed models to interrogate and strategies to mitigate CAR T cell exhaustion. HLA Typing: Purpose, Procedure, Interpretation - Verywell Health Opin. 205, 543555 (2008). To obtain Immunological exhaustion has indeed been characterized as one of the causes by which disease tolerance is achieved [97]. These approaches use different criteria and do not always overlap. Ghoneim, H. E. et al. et al. Proc. ISSN 1474-1733 (print). In a spatially resolved transcriptomic analysis of tumor from patients with cholangiocarcinoma, Wu et al. Some transcription factors have been interpreted as favoring exhaustion, for example, B lymphocyteinduced maturation protein 1 (Blimp-1), Eomesodermin (Eomes), Tox, and IRF4 (reviewed in [41]). 17, 11871196 (2016). 7, 8390 (2009). One such additional cause is the cytokine environment, with a typical focus on IL-10 and TGF- (which tend to favor exhaustion) [29,33,34] as well as IL-21 (which, in contrast, tends to inhibit exhaustion) [35]. Med. Dev. Nat. Frohlich, A. et al. Nat. J. Virol. Saying that exhaustion is associated with a cluster of markers without being able to specify which is unsatisfactory. Nat. Immunity 31, 283295 (2009). You are using a browser version with limited support for CSS. 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. Later, some papers insisted on the crucial importance of high antigen load in the characterization of exhaustion, with or without an accompanying mention of chronicity [21,29,32]. These PD-1+CD8+ T cells resemble stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells [9]. Another significant (and related) challenge is that exhaustion in the functional sense is not always caused by exposure to high doses of antigen. 168, 22472254 (2002). cognitive test measuring fecal microbiome and virome, blood immune markers. Open Access Mol. What is meant by dysfunction here is that some T cells, after activation and proliferation, do not fulfill the functions they are expected to perform as effector T cellstypically, they fail to eliminate infected cells and control the virus. One difficulty is that authors tend to overlook specifying which approach they have in mind when they qualify cells as exhausted. A second even more serious difficulty is that authors often act as if these 3 approaches necessarily aligned (i.e., as if the 3 properties always occurred jointly), when in fact they dont. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Natl Acad. Pauken, K. E. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. et al. Jadhav, R. R. et al. & Katsikis, P.D. Competing interests: The authors have declared that no competing interests exist. Targeting exhaustion in cancer therapies means different things depending on the approach to immunological exhaustion one adopts. & Riley, J.L. Google Scholar. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Liu, X. et al. PubMed Immunol. In contrast, the deletion of IRF4 in CD4 T cells resulted in dysfunction and graft tolerance, which means that, when expressed, IRF4 represses PD-1 and Helios [64] and favors reactivity to the allograft. N.P.R. E.L. receives preclinical research funding from Bristol-Myers Squibb. Google Scholar. Rev. . Rachel C. Lynn is an associate director of research at Lyell Immunopharma. Jin, X. et al. 9, 540547 (2003). Med. Exhausted cells transferred into a naive host can reexpand and protect it against the same pathogenic challenge [23], suggesting that such cells are not irreversibly dysfunctional, and this restoration is now known to occur through the stem-like exhausted cells [9]. PubMed Second, even in the limited number of cases in which there is a satisfactory overlap between the 3 approaches to immunological exhaustion (dysfunction, causes, and markers), focusing on exhaustion remains problematic because it constitutes at best a small subset of the many forms of immunological tolerance to the tumor. 85, 205214 (2009). For example, in patients with non-small cell lung cancer, hepatocellular carcinoma, and glioblastoma [28,51], or during pregnancy [52], there is no kinetic approach that would establish whether the chronic exposure to tumor or fetal antigens played a role in the induction of T-infiltrating or peripheral blood lymphocyte exhaustion. & Ahmed, R. Redefining chronic viral infection. Markers of Immune Cell Exhaustion as Predictor of Survival in He is Professor of Haematology/Oncology at the University of Regensburg, Germany, and received an MBA degree from the University of Warwick, UK. Sci. In those contexts, PD-1 was not always associated with cellular dysfunction, and it was even sometimes associated with an increased memory response [57,58]. Jameson, S.C. & Masopust, D. Diversity in T cell memory: an embarrassment of riches. Opin. Immunol. 1, eaai8593 (2016). Tinoco, R., Alcalde, V., Yang, Y., Sauer, K. & Zuniga, E.I. Li, H. et al. Khan, O. et al. 185, 498506 (2011). Natl. Ahrends, T. et al. & Frelinger, J.A. Overall, assuming an overlap between dysfunction on the one hand and chronicity and/or high antigen load on the other when predicting T-cell exhaustion and thus anti-PD1 response would lead to unsuitable therapeutic strategies. PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US. This is a preview of subscription content, access via your institution. Science 324, 15721576 (2009). 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. 14, 768774 (2014). As we will see, even the seemingly consensual view that antigen chronicity is the leading cause of exhaustion is questionable, including in the historically paradigmatic LCMV example. Annu. Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice. For example, although this dysfunction has sometimes been conceived as involving an incapacity for maintenance and expansion [1517], some T-cell populations (the stem-like CD8+ exhausted T-cell subset [18]) can persist and expand in chronic infections [13]. 203, 22812292 (2006). Acad. Three different approaches to immunological exhaustion. 182, 66976708 (2009). Nature 537, 417421 (2016). Benjamin A. Youngblood is an associate member in the Department of Immunology at St Jude Childrens Research Hospital. Nakamoto, N. et al. Natl. Is exhaustion always dysfunctional? Rev. According to the third approach, exhaustion is the cell state associated with the expression of particular molecular markersclassically inhibitory receptors. The TCF1Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Internet Explorer). Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Nature 557, 575579 (2018). 84, 16561663 (2010). Nature 458, 206210 (2009). We also propose to talk about exhaustion for and only for the phenomena in which all 3 approaches are aligned. Revisiting Immune Exhaustion During HIV Infection - PMC e1009892. Bengsch, B. et al. J. Virol. Med. nCounter Immune Exhaustion Panel - NanoString contracts here. McKinney, E. F., Lee, J. C., Jayne, D. R., Lyons, P. A. Immune activation and exhaustion marker expression on T-cell subsets in ART-treated adolescents and young adults with perinatal HIV-1 infection as correlates of viral persistence Finally, the metabolic changes observed in exhausted T cells can also occur in the tumor microenvironment through causes distinct from antigen chronicity and high antigen load [65]. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor that can suppress HCV-specific T-cell responses. Chemnitz, J.M., Parry, R.V., Nichols, K.E., June, C.H. Joshi, N.S. Nature 571, 211218 (2019). Crucially, even when focusing on one specific and explicitly described approach to exhaustion, many important difficulties remain. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. Google Scholar. PubMed Immunity 35, 400412 (2011). et al. Natl. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. 19, 408415 (2007). The claim that targeting dysfunctional T cells in cancer is equivalent to targeting exhausted T cells is, however, problematic for at least 2 fundamental reasons. Nicholas P. Restifo was trained at Memorial Sloan Kettering Cancer Center and was a principal investigator at the National Cancer Institute. Immunity 47, 848861 (2017).
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