Mohamed S. Abdel-Hakeem- 1Department of Pathology and Laboratory Medicine, and Emory Vaccine Center, Emory School of Medicine, Emory University, Atlanta, GA, United States
- 2Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
Editorial on the Research Topic
T cell exhaustion; mechanisms of induction, modulation, and recovery
Introduction
The current definition of T cell exhaustion has been coined in the immunology literature since 2003 (1). Exhaustion describes the differentiation pathway of T cells subjected to persistent antigenic stimulation during chronic viral infection and cancer (2). Exhausted T cells (TEX) are characterized by sustained elevated expression of inhibitory receptors (IRs), associated with progressive hierarchical loss of effector functions (1). Thus, IR-blockade represented a promising strategy to reinvigorate TEX (3). Indeed, checkpoint blockade revolutionized immunotherapy against cancer and cured patients resistant to classical therapeutic interventions (4).
Despite 20 years of profiling TEX cellularly, functionally, and transcriptionally, it is only in recent years that studies characterized the epigenetic profile (5–7) and subset dynamics of TEX (8–11), as well as the interplay of several transcription factors (TFs) in the exhaustion program (12–14). Deeper insights into TEX biology would unravel novel immunotherapeutic strategies. Seven research manuscripts and reviews in this Research Topic shed light on several aspects of T cell exhaustion.
Insights into TEX subset dynamics from HCV
Hepatitis C virus (HCV) infection is unique as the only human chronic viral infection where ~20-25% of patients spontaneously resolve the infection during the acute phase (rHCV), whereas most patients develop chronic disease (cHCV) (15). Another unique aspect of HCV is that it is now curable using direct-acting antivirals with ~95% sustained virologic response (SVR) success rate (15). Wildner et al. show that the master TF regulating exhaustion, TOX, was expressed in CD8 TEX across all disease stages and groups of patients, but at various levels. However, expression of another TF, eomesodermin (Eomes), was significantly higher in cHCV in T cells targeting unmutated epitopes compared to “off-target” T cells where the epitope underwent escape mutations inhibiting recognition by epitope-specific CD8 T cells. TOX-Eomes co-expression was associated with a more terminally differentiated phenotype of TEX (PD1hi CD39hi CD73lo CD127–) versus CD39lo CD73hi CD127+ phenotype characteristic of the progenitor TEX subset. SVR patients showed a mixed phenotype, which retains the expression of Eomes and IRs, while expressing the memory associated markers CD127 and CD73 characteristic of rHCV. This opens a new venue for investigating the modulation of TEX differentiation and subset dynamics by TOX-interactions with Eomes which is relatively understudied.
Immune pressure by T cells drives mutation of their cognate viral epitopes (15), however it is not known how this in return affects TEX phenotype. Osuch et al. add another layer to factors shaping TEX phenotype, as they show that epitope polymorphism within HCV impacts TEX subset dynamics. Interestingly, for some epitopes (e.g. NS1406) variations from the genotype-specific consensus sequence were associated with higher frequency of more terminally differentiated PD1+Tim-3+ TEX, however for other epitopes (e.g. NS1073) it was the contrary. These findings highlight the importance of dissecting TEX subset dynamics within the context of the autologous epitope sequences.
TEX reinvigoration; targeting PSGL-1, CD226, CD137, metabolism, and Tregs
As checkpoint blockade revolutionized immunotherapy, and the list of IRs keeps growing (16), more IRs are being targeted for TEX reinvigoration. The discovery of the inhibitory effects of PSGL-1 on TEX suggested immunotherapeutic potential (17). In this Research Topic, Viramontes et al. show that PSGL-1 modulates TEX biology in multiple ways. Deleting PSGL-1-encoding gene (Selplg–/–) confirmed its role in curtailing expansion of CD8 TEX, but at the same time showed it importance in maintaining virus/tumor-specific T cells, and the differentiation of the progenitor TEX subset. This highlights the potential of targeting PSGL-1 as a promising immunotherapeutic strategy, which was demonstrated by the same group in combination with PD1-blockade in a mouse melanoma model (18).
Another important aspect of TEX deviation from the acute differentiation path is adopting a different metabolic lifestyle (19), which was confirmed in consequent studies (20, 21). In the context of HIV, Alrubayyi et al. demonstrate that viremic individuals showed a more terminally differentiated phenotype of TEX (PD1hi Eomeshi TIGIT+) compared to Elite Controllers who naturally controlled HIV viremia. Importantly, this was associated with higher expression of Glut-1 glucose transporter, impaired mitochondrial function, and mitochondrial biogenesis. Multipronged treatment with a scavenger of reactive oxygen species (ROS), pharmacological inhibitors of dysregulated mitochondrial respiratory capacity, and interleukin-15 (IL-15) that enhances mitochondrial biogenesis promoted partial functional restoration of HIV-specific TEX.
Two significant reviews address points that are not commonly tackled when discussing CD8 T cell exhaustion. Pichler et al. discussed targeting less-studied co-stimulatory molecules such as CD226 and CD137, and signaling pathways such as phosphoinositide-3 (PI3) kinase for modulating TEX. As well as novel methods to enhance the stem-like/progenitor TCF1+ TEX subset which is the main subset responding to immunotherapy (22). McRitchie and Akkaya focus on one of the extrinsic factors affecting CD8 T cell exhaustion, which is CD4 regulatory T cells (Tregs). They specifically elaborate on the implication of Tregs within the tumor microenvironment (TME) on TEX, and the factors that promote the migration and immunosuppressive functions of Tregs.
TEX beyond chronic infection and cancer
An important implication of TEX is their role in the pathology of pharmacological diseases other than cancer or chronic viral infection. One example is atherosclerosis, the main underlying cause of coronary artery disease (CAD) (23, 24). Zhao et al. use computational biology tools, such as gene set variation analysis (GSVA), to identify hub genes associated with CD8 T cells in the context of CAD, that are shared with TEX signatures from multiple cancers. This identified biomarkers for CD8 T cells associated with CAD, and highlights the importance of monitoring TEX features for CAD.
Conclusion
Overall, the articles in this Research Topic highlight the pivotal role of TEX in a wide range of diseases and underscore the importance of deciphering more aspects of TEX biology and the factors modulating the exhaustion program. This is pivotal to inform the design of next generation immunotherapies. The majority of articles highlighted the importance of dissecting the underlying TEX subset dynamics when studying these aspects and factors.
Author contributions
The author confirms being the sole contributor of this work and has approved it for publication.
Acknowledgments
M.A-H is a Co-Investigator at the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative from CIHR (NHC-142832) and the Public Health Agency of Canada.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol (2003) 77:4911–27. doi: 10.1128/JVI.77.8.4911-4927.2003
2. McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol (2019) 37:457–95. doi: 10.1146/annurev-immunol-041015-055318
3. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature (2006) 439:682–7. doi: 10.1038/nature04444
4. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science (2018) 359:1350–5. doi: 10.1126/science.aar4060
5. Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P, Dogra P, et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell (2017) 170:142–57 e19. doi: 10.1016/j.cell.2017.06.007
6. Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science (2016) 354:1160–5. doi: 10.1126/science.aaf2807
7. Philip M, Fairchild L, Sun L, Horste EL, Camara S, Shakiba M, et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature (2017) 545:452–6. doi: 10.1038/nature22367
8. Beltra JC, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, et al. Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity (2020) 52:825–41 e8. doi: 10.1016/j.immuni.2020.04.014
9. Hudson WH, Gensheimer J, Hashimoto M, Wieland A, Valanparambil RM, Li P, et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1(+) stem-like CD8(+) T cells during chronic infection. Immunity (2019) 51:1043–58 e4. doi: 10.1016/j.immuni.2019.11.002
10. Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, et al. T Cell factor 1-expressing memory-like CD8(+) T cells sustain the immune response to chronic viral infections. Immunity (2016) 45:415–27. doi: 10.1016/j.immuni.2016.07.021
11. Zander R, Schauder D, Xin G, Nguyen C, Wu X, Zajac A, et al. CD4(+) T cell help is required for the formation of a cytolytic CD8(+) T cell subset that protects against chronic infection and cancer. Immunity (2019) 51:1028–42 e4. doi: 10.1016/j.immuni.2019.10.009
12. Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature (2019) 571:265–9. doi: 10.1038/s41586-019-1326-9
13. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature (2019) 571:211–8. doi: 10.1038/s41586-019-1325-x
14. Scott AC, Dundar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M, et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature (2019) 571:270–4. doi: 10.1038/s41586-019-1324-y
15. Shoukry NH, Walker CM. T Cell responses during HBV and HCV infections: similar but not quite the same? Curr Opin Virol (2021) 51:80–6. doi: 10.1016/j.coviro.2021.08.011
16. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol (2009) 10:29–37. doi: 10.1038/ni.1679
17. Tinoco R, Carrette F, Barraza ML, Otero DC, Magana J, Bosenberg MW, et al. PSGL-1 is an immune checkpoint regulator that promotes T cell exhaustion. Immunity (2016) 44:1190–203. doi: 10.1016/j.immuni.2016.04.015
18. DeRogatis JM, Viramontes KM, Neubert EN, Henriquez ML, Guerrero-Juarez CF, Tinoco R. Targeting the PSGL-1 immune checkpoint promotes immunity to PD-1-Resistant melanoma. Cancer Immunol Res (2022) 10:612–25. doi: 10.1158/2326-6066.CIR-21-0690
19. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S, Kalia V, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity (2007) 27:670–84. doi: 10.1016/j.immuni.2007.09.006
20. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity (2016) 45:358–73. doi: 10.1016/j.immuni.2016.07.008
21. Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity (2016) 45:374–88. doi: 10.1016/j.immuni.2016.07.009
22. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature (2016) 537:417–21. doi: 10.1038/nature19330
23. Bergstrom I, Backteman K, Lundberg A, Ernerudh J, Jonasson L. Persistent accumulation of interferon-gamma-producing CD8+CD56+ T cells in blood from patients with coronary artery disease. Atherosclerosis (2012) 224:515–20. doi: 10.1016/j.atherosclerosis.2012.07.033
Keywords: T cell exhaustion, Tex subsets, Tex reinvigoration, regulatory T cells (Tregs), exhaustion signature in CAD
Citation: Abdel-Hakeem MS (2023) Editorial: T cell exhaustion; mechanisms of induction, modulation, and recovery. Front. Immunol. 13:1122530. doi: 10.3389/fimmu.2022.1122530
Received: 13 December 2022; Accepted: 19 December 2022;
Published: 05 January 2023.
Edited and Reviewed by:
Allan Zajac, University of Alabama at Birmingham, United StatesCopyright © 2023 Abdel-Hakeem. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mohamed S. Abdel-Hakeem, bS5oYWtlZW1AZW1vcnkuZWR1