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      Functional Characterization of Ly49 +CD8 T-Cells in Both Normal Condition and During Anti-Viral Response

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          Abstract

          The role of Ly49 +CD8 T-cells in the immune system is not clear. Previously, several papers suggested Ly49 +CD8 T-cells as immunosuppressors, while multiple studies also suggested their role as potent participants of the immune response. The mechanism of Ly49 expression on CD8 T-cells is also not clear. We investigated phenotype, functions, and regulation of Ly49 expression on murine CD8 T-cells in both normal state and during LCMV infection. CD8 T-cells express different Ly49 receptors compared with NK-cells. In intact mice, Ly49 +CD8 T-cells have a phenotype similar to resting central memory CD8 T-cells and do not show impaired proliferation and cytokine production. Conventional CD8 T-cells upregulate Ly49 receptors during TCR-induced stimulation, and IL-2, as well as IL-15, affect it. At the same time, Ly49 +CD8 T-cells change the Ly49 expression profile dramatically upon re-stimulation downregulating inhibitory and upregulating activating Ly49 receptors. We observed the expression of Ly49 receptors on the virus-specific CD8 T-cells during LCMV infection, especially marked in the early stages, and participation of Ly49 +CD8 T-cells in the anti-viral response. Thus, CD8 T-cells acquire Ly49 receptors during the T-cell activation and show dynamic regulation of Ly49 receptors during stimulation.

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          Most cited references46

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          Opposing T Cell Responses in Experimental Autoimmune Encephalomyelitis

          In experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), induction generates successive waves of clonally expanded CD4+, CD8+, and γ+ T cells in the blood and central nervous system, similar to gluten challenge studies of Celiac patients. In MS patients, we also observe major expansions of CD8+ T cells. In EAE, we find that most expanded CD4+ T cells are specific for the inducing myelin peptide MOG35–55 but in contrast, surrogate peptides derived from a yeast peptide-MHC display library for some of the clonally expanded CD8+ T cells inhibit disease by suppressing the proliferation of MOG-specific CD4+ T cells. These results suggest the induction of autoreactive CD4+ T cells triggers an opposing mobilization of regulatory CD8+ T cells.
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            CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice.

            The immune system includes a subpopulation of CD8(+) T cells equipped to inhibit the expansion of follicular T helper (T(FH)) cells, resulting in suppression of autoantibody production and associated lupus-like disease. These CD8(+) T regulatory (Treg) cells recognize Qa-1/peptide complexes on target T(FH) cells and depend on the IL-15 cytokine for development and function. Here we show that these CD8(+) Treg cells express a triad of surface receptors--CD44, CD122, and the class I MHC receptor Ly49--and account for <5% of CD8(+) T cells. Moreover, the development of systemic lupus erythematosus-like disease in B6-Yaa mutant mice is associated with a pronounced defect in CD8(+) Treg cell activity, suggesting that this regulatory subset may represent an effective therapeutic approach to systemic lupus erythematosus-like autoimmune disease.
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              Interleukin 15 Controls both Proliferation and Survival of a Subset of Memory-Phenotype CD8+ T Cells

              Previous work has shown that memory-phenotype CD44hi CD8+ cells are controlled by a cytokine, interleukin (IL)-15. However, the dependency of CD44hi CD8+ cells on IL-15 is partial rather than complete. Here, evidence is presented that CD44hi CD8+ cells comprise a mixed population of IL-15–dependent and IL-15–independent cells. The major subset of CD122hi CD44hi CD8+ cells is heavily dependent on IL-15 by three different parameters, namely (1) “bystander” proliferation induced via IFN-induced stimulation of the innate immune system, (2) normal “background” proliferation, and (3) T cell survival; IL-15 dependency is most extreme for the Ly49+ subset of CD122hi CD44hi CD8+ cells. In contrast to CD122hi cells, the CD122lo subset of CD44hi CD8+ cells is IL-15 independent; likewise, being CD122lo, CD44hi CD4+ cells are IL-15 independent. Thus, subsets of memory-phenotype T cells differ radically in their sensitivity to IL-15.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                07 January 2021
                2020
                : 11
                : 602783
                Affiliations
                [1] 1 Institute of Immunology, School of Medicine, Zhejiang University , Hangzhou, China
                [2] 2 Zhejiang University-University of Edinburgh Institute, Zhejiang University , Haining, China
                [3] 3 Department of Immunology and Rheumatology in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine , Hangzhou, China
                Author notes

                Edited by: Nick Gascoigne, National University of Singapore, Singapore

                Reviewed by: Harvey Cantor, Dana–Farber Cancer Institute, United States; Serena Meraviglia, University of Palermo, Italy; Joanna Brzostek, University of Freiburg, Germany

                *Correspondence: Linrong Lu, lu_linrong@ 123456zju.edu.cn

                †These authors have contributed equally to this work

                This article was submitted to T Cell Biology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.602783
                7817614
                a40d1930-a4f9-48bc-ab9c-cbc3b528e5fd
                Copyright © 2021 Shytikov, Rohila, Li, Wang, Jiang, Zhang, Xu and Lu

                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.

                History
                : 04 September 2020
                : 20 November 2020
                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 46, Pages: 15, Words: 7662
                Categories
                Immunology
                Original Research

                Immunology
                cd8 t-cells,memory phenotype,nk-cell receptors,ly49 receptors,anti-viral response
                Immunology
                cd8 t-cells, memory phenotype, nk-cell receptors, ly49 receptors, anti-viral response

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