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      SLAMF7 defines subsets of human effector CD8 T cells

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          Abstract

          Long-term control of viral replication relies on the efficient differentiation of memory T cells into effector T cells during secondary immune responses. Recent findings have identified T cell precursors for both memory and exhausted T cells, suggesting the existence of progenitor-like effector T cells. These cells can persist without antigenic challenge but expand and acquire effector functions upon recall immune responses. In this study, we demonstrate that the combination of SLAMF7 with either CD27 or TCF-1 effectively identifies progenitor-like effector CD8 T cells, while SLAMF7 with GPR56 or TOX defines effector CD8 T cells. These markers allow for the clear segregation of these distinct cell subsets. SLAMF7 + CD8T cells are dynamically modulated during viral infections, including HIV, HCV, CMV, and SARS-CoV-2, as well as during aging. We further characterize the SLAMF7 signature at both phenotypic and transcriptional levels. Notably, during aging, the SLAMF7 pathway becomes dysregulated, resulting in persistent phosphorylation of STAT1. Additionally, SLAMF7 ligation in the presence of IL-15 induces TCF-1 expression, which promotes the homeostatic proliferation of progenitor-like effector CD8 T cells.

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          Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

          Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8 + T cells were defined by clustering, and associated with patient tumor regression or progression. A single transcription factor, TCF7 , was visualized within CD8 + T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states, and demonstrated enhanced anti-tumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms and targets for enhancing checkpoint immunotherapy. Single cell analysis of immune cells from melanoma uncovers a TCF7+ memory-like state in the cytotoxic T cell population, and demonstrates its association with a positive outcome
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            Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy

            Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8+ T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal differentiation or exhaustion of tumor-specific T cells. Here we identified a subset of tumor-reactive TILs bearing hallmarks of exhausted cells and central memory cells, including expression of the checkpoint protein PD-1 and the transcription factor Tcf1. Tcf1+PD-1+ TILs mediated the proliferative response to immunotherapy, generating both Tcf1+PD-1+ and differentiated Tcf1-PD-1+ cells. Ablation of Tcf1+PD-1+ TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1+PD-1+ TILs but was essential for the stem-like functions of these cells. Human TCF1+PD-1+ cells were detected among tumor-reactive CD8+ T cells in the blood of melanoma patients and among TILs of primary melanomas. Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.
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              TOX transcriptionally and epigenetically programs CD8 + T cell exhaustion

              SUMMARY Exhausted CD8+ T cells (TEX) in chronic infections and cancer have limited effector function, high inhibitory receptor co-expression and extensive transcriptional changes compared to effector (TEFF) or memory (TMEM) CD8+ T cells. TEX are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, TEX are a distinct immune subset, with a unique chromatin landscape compared to TEFF and TMEM. However, the mechanisms governing the transcriptional and epigenetic development of TEX remain unknown. Here, we identify the HMG-box transcription factor TOX as a central regulator of TEX. TOX is largely dispensable for TEFF and TMEM formation, but is critical for exhaustion and without TOX TEX do not form. TOX is induced by calcineurin and NFAT2 and operates in a feed-forward loop to become calcineurin independent and sustained in TEX. Thus, robust TOX expression results in commitment to TEX by translating persistent stimulation into a distinct TEX transcriptional and epigenetic developmental program.
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                Author and article information

                Contributors
                kared.hassen@gmail.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                28 December 2024
                28 December 2024
                2024
                : 14
                : 30779
                Affiliations
                [1 ]Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), ( https://ror.org/03vmmgg57) Immunos Building, 8A Biomedical Grove, Biopolis, Republic of Singapore
                [2 ]Department of Immunology, Oslo University Hospital, ( https://ror.org/00j9c2840) Oslo, Norway
                [3 ]Precision Immunotherapy Alliance, University of Oslo, ( https://ror.org/01xtthb56) Oslo, Norway
                [4 ]Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, ( https://ror.org/04vfhnm78) Seville, Spain
                [5 ]Centre of Excellence for Research in AIDS (CERiA), University of Malaya, ( https://ror.org/00rzspn62) Kuala Lumpur, Malaysia
                [6 ]The Peter Doherty Institute for Infection and Immunity, University of Melbourne, ( https://ror.org/01ej9dk98) Melbourne, Australia
                [7 ]Faculty of Medicine, University of Malaya, ( https://ror.org/00rzspn62) Kuala Lumpur, Malaysia
                [8 ]Gerontology Research Programme and Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, Singapore
                [9 ]Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, ( https://ror.org/01tgyzw49) Singapore, Republic of Singapore
                Article
                80971
                10.1038/s41598-024-80971-5
                11680708
                39730488
                0aeb9793-3d8d-4802-b3e4-08f490c10ec7
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

                History
                : 8 July 2024
                : 22 November 2024
                Funding
                Funded by: FundRef 501100001348, Agency for Science, Technology and Research (A*STAR);
                Award ID: No. 10-036
                Award ID: BMRC IAF 311006, BMRC transition funds#H16/99/b0/011, BMRC IAF-PP H1901a0024
                Award Recipient :
                Funded by: NRF Singapore, (NRF SIS) NRF2017_SISFP09.
                Funded by: FundRef 501100004587, Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III);
                Award ID: PI16/00684
                Award ID: PI9/01127
                Award Recipient :
                Funded by: FundRef 501100003093, Ministry of Higher Education, Malaysia (MOHE);
                Award ID: HIR/MOHE; H-20001-E000001
                Funded by: FundRef 501100004386, Universiti Malaya (University of Malaya);
                Award ID: UMRG RP029-14HTM
                Award Recipient :
                Categories
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                © Springer Nature Limited 2024

                Uncategorized
                viral infection,lymphocyte differentiation
                Uncategorized
                viral infection, lymphocyte differentiation

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