Editorial: Tissue Resident Memory T Cells
- 1INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, EPHE, PSL, Fac. de Médecine – Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France
- 2INSERM U970, PARCC (Paris Centre de Recherche Cardiovasculaire), Université Paris Descartes, Paris, France
- 3Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, Paris, France
Editorial on the Research Topic
Tissue Resident Memory T Cells
Resident memory T cells (TRM) were identified about 10 years ago following the discovery of tissue-resident T cells that do not recirculate. The role of this population of T cells in control of viral infections was rapidly demonstrated. This population is considered to represent a new T-lymphocyte lineage, in that it lacks molecules enabling egress from the tissue and migration to lymph nodes (Klf2, S1Pr1, CCR7, CD62L, etc.) and expresses specific markers of residency (CD103, CD49a, CD69). However, not all TRM cells express these surface markers and their residency feature remains the main characteristic. TRM cells have a distinct differentiation profile dependent on certain cytokines (TGF-β, IL-15, Type I IFN, IL-12) and specific transcription factors (Runx3, Hobit, Blimp-1, Notch, etc.) [Behr et al., (1)]. More than 130 articles were published in 2018 on this population, covering all areas of pathology (infection, allergy, autoimmunity, transplantation, cancer, etc.). The moment thus seemed appropriate for publishing a special issue on this T-cell subset so as to elucidate our current state of knowledge, as well as exploring less frequently addressed issues, such as the specific metabolism of TRM cells (Pan and Kupper), subpopulations of CD4+ TRM (Oja et al., Wilk and Mills) and resident lymphocyte populations different from conventional T cells, such as innate lymphocytes or innate-like cells (Chou and Li). The major niches for TRM maintenance and persistence, which is an important issue for this population, are also discussed (Takamura). It is interesting to note that, while this T-cell subset was initially studied in the context of infectious diseases, its role in oncology has recently been demonstrated (2–5). Nevertheless, in the present special issue, the number of articles and reviews dedicated to TRM cells in infection (Wilk and Mills, Morabitoet et al., Muruganandah et al.) is fewer than those dealing with their role in cancer diseases (Oja et al., Blanc et al., Corgnac et al., Dhodapkar, Dumauthioz et al., Smazynski and Webb). This is not surprising; indeed, cancer immunotherapy targets the tumor microenvironment in which TRM cells are located, presumably due to their expression of CD103 integrin, allowing an interaction with tumor epithelial cells expressing E-cadherin (6–11).
The search for cellular targets mediating the therapeutic effects of anti-PD-1 and anti-PD-L1 antibodies is the subject of intense worldwide investigation. This is a medical challenge, and goes hand in hand with the identification of biomarkers predictive of a response to these immunotherapies so as to more effectively select patients likely to respond. The role of TRM has been rapidly addressed; indeed, they represent cells that express high levels of inhibitory receptors (PD-1, Tim-3, etc.) (2, 12), and it has been shown that these lymphocytes proliferate after treatment with anti-PD-1/-PD-L1 (13). Despite expression of high levels of checkpoint receptors, these cells have a cytotoxic capacity, especially after blocking of the PD-1-PD-L1 axis, indicating that they can be reactivated (2, 14). Expression by TRM cells of high levels of granzyme B and TNF-α, as well as the presence of preformed RNA coding for IFNγ, may explain the particular reactivity of these lymphocytes (Behr et al.). A strongly documented hypothesis concerning the mechanism of action of anti-PD-1/-PD-L1 relies on the presence of pre-existing anti-tumor T cells (15, 16). Interestingly, when TRM (CD103+CD8+ T cells) were separated from the other T cells isolated from the tumor microenvironment, these lymphocytes were enriched in tumor-specific cells (2, 12). In different preclinical tumor models, the presence of these T lymphocytes enables maintaining an equilibrium between the host and tumor, and protects against cancer progression (17). In line with these previous results, mice deficient in TRM cells display accelerated tumor growth (17). In humans, tumor infiltration with this T-cell subset is associated with a favorable prognosis in both univariate and multivariate (2, 12, 14, 18) analyses. TRM cells can be characterized by different techniques (transcriptomic, single cell RNAseq, cytof, etc.) requiring high quality when performing cell isolation. In the present issue, Rissiek et al. report that blocking ARTC2.2 by preventing P2X7 ribosylation improves cell vitality during their ex vivo isolation.
Various reviews in this issue are also devoted to a better understanding of mechanisms involved in TRM differentiation in vivo and new strategies for inducing them, especially after vaccination (Morabito et al., Muruganandah et al.). TRM cells can be generated from naive T lymphocytes, and a TRM precursor phenotype (KLRG1low) has been reported (19). Nevertheless, central memory T (TCM) cells and effector T (TEFF) cells can also differentiate into TRM cells in peripheral tissue, suggesting a certain plasticity of the pool of memory T lymphocytes (Enamorado et al.). This mode of generation may explain why a common T-cell receptor (TCR) repertoire has been pointed out between TCM cells and TRM cells (20). Differentiation of TRM cells can be inhibited using an anti-TGF-β or an inhibitor of the mTor pathway during T-cell priming (12, 21). Specific parameters might influence generation of TRM, such as the high affinity of TCR for the HLA-Class I-peptide complex or a strong inflammatory stimulus (22, 23). In some tissues, but not in others, such as the lung, it has been shown that an inflammatory stimulus without the presence of the antigen may be sufficient to induce differentiation of TRM (5). Finally, in mice, Batf3-dependent type I dendritic cells (DC), corresponding to DNGR-1-expressing DC, appear to be required for priming of TRM (24). In contrast, in humans, CD1c+ DC and, to a lesser extent, CD141+ DC, play a crucial role in differentiation of TRM cells (25). The need for these local DCs for priming T lymphocytes may explain why the mucosal route of immunization is most effective in priming TRM (26, 27). Vectors targeting certain DC subtypes (4, 28) and some mucosal adjuvants (IL-1β, αGalCer, zymosan. etc.) also boost generation of TRM cells (29–31). The present issue provides the most up-to-date information on TRM cells, but the field is very rapidly evolving. A recent article from Neurath MG's group shows that CD4 TRM cells also play a pathogenic role in models of intestinal inflammation, thus opening up a new field of investigation and indicating a direct role for these lymphocytes in human pathologies (32).
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
This work was supported by grants from the Association pour la Recherche sur le Cancer (ARC), Fondation ARC, the Institut national du Cancer (INCa, PLBio), Labex Immuno-Oncology, SIRIC-CARPEM, SIRIC-SOCRATE and Ligue contre le Cancer.
Conflict of Interest Statement
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.
We acknowledge all the authors that contributed to this special issue on TRM cells.
2. Djenidi F, Adam J, Goubar A, Durgeau A, Meurice G, de Montpreville V, et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J Immunol. (2015) 194:3475–86. doi: 10.4049/jimmunol.1402711
3. Mami-Chouaib F, Blanc C, Corgnac S, Hans S, Malenica I, Granier C, et al. Resident memory T cells, critical components in tumor immunology. J Immunother Cancer. (2018) 6:87. doi: 10.1186/s40425-018-0399-6
4. Sandoval F, Terme M, Nizard M, Badoual C, Bureau MF, Freyburger L, et al. Mucosal imprinting of vaccine-induced CD8+ T cells is crucial to inhibit the growth of mucosal tumors. Sci Transl Med. (2013) 5:172ra20. doi: 10.1126/scitranslmed.3004888
5. Enamorado M, Iborra S, Priego E, Cueto FJ, Quintana JA, Martinez-Cano S, et al. Enhanced anti-tumour immunity requires the interplay between resident and circulating memory CD8+ T cells. Nat Commun. (2017) 8:16073. doi: 10.1038/ncomms16073
6. Franciszkiewicz K, Le Floc'h A, Jalil A, Vigant F, Robert T, Vergnon I, et al. Intratumoral induction of CD103 triggers tumor-specific CTL function and CCR5-dependent T-cell retention. Cancer Res. (2009) 69:6249–55. doi: 10.1158/0008-5472.CAN-08-3571
7. Franciszkiewicz K, Le Floc'h A, Boutet M, Vergnon I, Schmitt A, Mami-Chouaib F. CD103 or LFA-1 engagement at the immune synapse between cytotoxic T cells and tumor cells promotes maturation and regulates T-cell effector functions. Cancer Res. (2013) 73:617–28. doi: 10.1158/0008-5472.CAN-12-2569
8. Le Floc'h A, Jalil A, Vergnon I, Le Maux Chansac B, Lazar V, Bismuth G, et al. Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. J Exp Med. (2007) 204:559–70. doi: 10.1084/jem.20061524
9. Le Floc'h A, Jalil A, Franciszkiewicz K, Validire P, Vergnon I, Mami-Chouaib F. Minimal engagement of CD103 on cytotoxic T lymphocytes with an E-cadherin-Fc molecule triggers lytic granule polarization via a phospholipase Cgamma-dependent pathway. Cancer Res. (2011) 71:328–38. doi: 10.1158/0008-5472.CAN-10-2457
10. Boutet M, Gauthier L, Leclerc M, Gros G, de Montpreville V, Theret N, et al. TGFbeta signaling intersects with CD103 integrin signaling to promote T-lymphocyte accumulation and antitumor activity in the lung tumor microenvironment. Cancer Res. (2016) 76:1757–69. doi: 10.1158/0008-5472.CAN-15-1545
11. Gauthier L, Corgnac S, Boutet M, Gros G, Validire P, Bismuth G, et al. Paxillin binding to the cytoplasmic domain of CD103 promotes cell adhesion and effector functions for CD8+ resident memory T cells in tumors. Cancer Res. (2017) 77:7072–82. doi: 10.1158/0008-5472.CAN-17-1487
13. Edwards J, Wilmott JS, Madore J, Gide TN, Quek C, Tasker A, et al. CD103+ Tumor-resident CD8+ T cells are associated with improved survival in immunotherapy-naive melanoma patients and expand significantly during anti-PD-1 treatment. Clin Cancer Res. (2018) 24:3036–45. doi: 10.1158/1078-0432.CCR-17-2257
14. Ganesan AP, Clarke J, Wood O, Garrido-Martin EM, Chee SJ, Mellows T, et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat Immunol. (2017) 18:940–50. doi: 10.1038/ni.3775
15. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. (2014) 515:568–71. doi: 10.1038/nature13954
16. Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. (2013) 73:128–38. doi: 10.1158/0008-5472.CAN-12-2606
17. Park SL, Buzzai A, Rautela J, Hor JL, Hochheiser K, Effern M, et al. Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin. Nature. (2019) 565:366–71. doi: 10.1038/s41586-018-0812-9
18. Savas P, Virassamy B, Ye C, Salim A, Mintoff CP, Caramia F, et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat Med. (2018) 24:986–93. doi: 10.1038/s41591-018-0078-7
19. Mackay LK, Rahimpour A, Ma JZ, Collins N, Stock AT, Hafon ML, et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat Immunol. (2013) 14:1294–301. doi: 10.1038/ni.2744
20. Gaide O, Emerson RO, Jiang X, Gulati N, Nizza S, Desmarais C, et al. Common clonal origin of central and resident memory T cells following skin immunization. Nat Med. (2015) 21:647–53. doi: 10.1038/nm.3860
21. Sowell RT, Rogozinska M, Nelson CE, Vezys V, Marzo AL. Cutting edge: generation of effector cells that localize to mucosal tissues and form resident memory CD8 T cells is controlled by mTOR. J Immunol. (2014) 193:2067–71. doi: 10.4049/jimmunol.1400074
22. Casey KA, Fraser KA, Schenkel JM, Moran A, Abt MC, Beura LK, et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J Immunol. (2012) 188:4866–75. doi: 10.4049/jimmunol.1200402
24. Iborra S, Martinez-Lopez M, Khouili SC, Enamorado M, Cueto FJ, Conde-Garrosa R, et al. Optimal generation of tissue-resident but not circulating memory T cells during viral infection requires crosspriming by DNGR-1+ dendritic cells. Immunity. (2016) 45:847–60. doi: 10.1016/j.immuni.2016.08.019
25. Yu CI, Becker C, Wang Y, Marches F, Helft J, Leboeuf M, et al. Human CD1c+ dendritic cells drive the differentiation of CD103+ CD8+ mucosal effector T cells via the cytokine TGF-beta. Immunity. (2013) 38:818–30. doi: 10.1016/j.immuni.2013.03.004
26. Granier C, Blanc C, Karaki S, Tran T, Roussel H, Tartour E. Tissue-resident memory T cells play a key role in the efficacy of cancer vaccines. Oncoimmunology. (2017) 6:e1358841. doi: 10.1080/2162402X.2017.1358841
27. Sun YY, Peng S, Han L, Qiu J, Song L, Tsai Y, et al. Local HPV recombinant vaccinia boost following priming with an HPV DNA vaccine enhances local HPV-specific CD8+ T-cell-mediated tumor control in the genital tract. Clin Cancer Res. (2016) 22:657–69. doi: 10.1158/1078-0432.CCR-15-0234
28. Wakim LM, Smith J, Caminschi I, Lahoud MH, Villadangos JA. Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection. Mucosal Immunol. (2015) 8:1060–71. doi: 10.1038/mi.2014.133
29. Caminschi I, Lahoud MH, Pizzolla A, Wakim LM. Zymosan by-passes the requirement for pulmonary antigen encounter in lung tissue-resident memory CD8+ T cell development. Mucosal Immunol. (2019) 12:403–12. doi: 10.1038/s41385-018-0124-2
30. Lapuente D, Storcksdieck Genannt Bonsmann M, Maaske A, Stab V, Heinecke V, Watzstedt K, et al. IL-1beta as mucosal vaccine adjuvant: the specific induction of tissue-resident memory T cells improves the heterosubtypic immunity against influenza A viruses. Mucosal Immunol. (2018) 11:1265–78. doi: 10.1038/s41385-018-0017-4
31. Nizard M, Diniz MO, Roussel H, Tran T, Ferreira LC, Badoual C, et al. Mucosal vaccines: novel strategies and applications for the control of pathogens and tumors at mucosal sites. Hum Vaccin Immunother. (2014) 10:2175–87. doi: 10.4161/hv.29269
Keywords: TRM cells, antitumor immune response, infectious diseases, T-cell immunity, CD103 integrin, TRM, resident memory T cells
Citation: Mami-Chouaib F and Tartour E (2019) Editorial: Tissue Resident Memory T Cells. Front. Immunol. 10:1018. doi: 10.3389/fimmu.2019.01018
Received: 01 April 2019; Accepted: 23 April 2019;
Published: 27 May 2019.
Edited and reviewed by: Scott N. Mueller, The University of Melbourne, Australia
Copyright © 2019 Mami-Chouaib and Tartour. 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.