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      Phenotype of NK-Like CD8(+) T Cells with Innate Features in Humans and Their Relevance in Cancer Diseases


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          Unconventional T cells are defined by their capacity to respond to signals other than the well-known complex of peptides and major histocompatibility complex proteins. Among the burgeoning family of unconventional T cells, innate-like CD8(+) T cells in the mouse were discovered in the early 2000s. This subset of CD8(+) T cells bears a memory phenotype without having encountered a foreign antigen and can respond to innate-like IL-12 + IL-18 stimulation. Although the concept of innate memory CD8(+) T cells is now well established in mice, whether an equivalent memory NK-like T-cell population exists in humans remains under debate. We recently reported that CD8(+) T cells responding to innate-like IL-12 + IL-18 stimulation and co-expressing the transcription factor Eomesodermin (Eomes) and KIR/NKG2A membrane receptors with a memory/EMRA phenotype may represent a new, functionally distinct innate T cell subset in humans. In this review, after a summary on the known innate CD8(+) T-cell features in the mouse, we propose Eomes together with KIR/NKG2A and CD49d as a signature to standardize the identification of this innate CD8(+) T-cell subset in humans. Next, we discuss IL-4 and IL-15 involvement in the generation of innate CD8(+) T cells and particularly its possible dependency on the promyelocytic leukemia zinc-finger factor expressing iNKT cells, an innate T cell subset well documented for its susceptibility to tumor immune subversion. After that, focusing on cancer diseases, we provide new insights into the potential role of these innate CD8(+) T cells in a physiopathological context in humans. Based on empirical data obtained in cases of chronic myeloid leukemia, a myeloproliferative syndrome controlled by the immune system, and in solid tumors, we observe both the possible contribution of innate CD8(+) T cells to cancer disease control and their susceptibility to tumor immune subversion. Finally, we note that during tumor progression, innate CD8(+) T lymphocytes could be controlled by immune checkpoints. This study significantly contributes to understanding of the role of NK-like CD8(+) T cells and raises the question of the possible involvement of an iNKT/innate CD8(+) T cell axis in cancer.

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          Most cited references57

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          Selective stimulation of T cell subsets with antibody-cytokine immune complexes.

          Interleukin-2 (IL-2), which is a growth factor for T lymphocytes, can also sometimes be inhibitory. Thus, the proliferation of CD8+ T cells in vivo is increased after the injection of a monoclonal antibody that is specific for IL-2 (IL-2 mAb), perhaps reflecting the removal of IL-2-dependent CD4+ T regulatory cells (T regs). Instead, we show here that IL-2 mAb augments the proliferation of CD8+ cells in mice simply by increasing the biological activity of preexisting IL-2 through the formation of immune complexes. When coupled with recombinant IL-2, some IL-2/IL-2 mAb complexes cause massive (>100-fold) expansion of CD8+ cells in vivo, whereas others selectively stimulate CD4+ T regs. Thus, different cytokine-antibody complexes can be used to selectively boost or inhibit the immune response.
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            Naive T Cells Transiently Acquire a Memory-like Phenotype during Homeostasis-Driven Proliferation

            In a depleted lymphoid compartment, naive T cells begin a slow proliferation that is independent of cognate antigen yet requires recognition of major histocompatibility complex–bound self-peptides. We have followed the phenotypic and functional changes that occur when naive CD8+ T cells undergo this type of expansion in a lymphopenic environment. Naive T cells undergoing homeostasis-driven proliferation convert to a phenotypic and functional state similar to that of memory T cells, yet distinct from antigen-activated effector T cells. Naive T cells dividing in a lymphopenic host upregulate CD44, CD122 (interleukin 2 receptor β) and Ly6C expression, acquire the ability to rapidly secrete interferon γ, and become cytotoxic effectors when stimulated with cognate antigen. The conversion of naive T cells to cells masquerading as memory cells in response to a homeostatic signal does not represent an irreversible differentiation. Once the cellularity of the lymphoid compartment is restored and the T cells cease their division, they regain the functional and phenotypic characteristics of naive T cells. Thus, homeostasis-driven proliferation provides a thymus-independent mechanism for restoration of the naive compartment after a loss of T cells.
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              Homeostasis-Stimulated Proliferation Drives Naive T Cells to Differentiate Directly into Memory T Cells

              The developmental requirements for immunological memory, a central feature of adaptive immune responses, is largely obscure. We show that as naive CD8 T cells undergo homeostasis-driven proliferation in lymphopenic mice in the absence of overt antigenic stimulation, they progressively acquire phenotypic and functional characteristics of antigen-induced memory CD8 T cells. Thus, the homeostasis-induced memory CD8 T cells express typical memory cell markers, lyse target cells directly in vitro and in vivo, respond to lower doses of antigen than naive cells, and secrete interferon γ faster upon restimulation. Like antigen-induced memory T cell differentiation, the homeostasis-driven process requires T cell proliferation and, initially, the presence of appropriate restricting major histocompatibility complexes, but it differs by occurring without effector cell formation and without requiring interleukin 2 or costimulation via CD28. These findings define repetitive cell division plus T cell receptor ligation as the basic requirements for naive to memory T cell differentiation.

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                27 March 2017
                : 8
                : 316
                [1] 1INSERM 1082 , Poitiers, France
                [2] 2CHU de Poitiers , Poitiers, France
                [3] 3Service d’Hématologie et d’Oncologie Biologique, CHU de Poitiers , Poitiers, France
                [4] 4Université de Poitiers , Poitiers, France
                [5] 5Service d’Immunologie et Inflammation, CHU de Poitiers , Poitiers, France
                [6] 6Institut Curie, PSL Research University, INSERM U932 , Paris, France
                [7] 7SiRIC Translational Immunotherapy Team, Translational Research Department, Research Center, Institut Curie, PSL Research University , Paris, France
                [8] 8Centre d’Investigation Clinique Biothérapie CICBT 1428, Institut Curie , Paris, France
                [9] 9INSERM U1242 , Rennes, France
                [10] 10CHU de Rennes , Rennes, France
                [11] 11INSERM U991 , Rennes, France
                [12] 12CRB Santé de Rennes , Rennes, France
                Author notes

                Edited by: Fernando A. Arosa, Universidade da Beira Interior, Portugal

                Reviewed by: Avery August, Cornell University, USA; Wilhelm Gerner, Veterinärmedizinische Universität, Austria

                *Correspondence: André Herbelin, andre.herbelin@ 123456inserm.fr ; Jean-Marc Gombert, jm.gombert@ 123456chu-poitiers.fr

                These authors have contributed equally to this work.

                These authors have contributed equally to this work as senior authors.

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

                Copyright © 2017 Barbarin, Cayssials, Jacomet, Nunez, Basbous, Lefèvre, Abdallah, Piccirilli, Morin, Lavoue, Catros, Piaggio, Herbelin and Gombert.

                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) or licensor 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.

                : 15 December 2016
                : 06 March 2017
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 74, Pages: 16, Words: 10442
                Hypothesis and Theory

                innate memory cd8(+) t cells,nk-like t cells,inkt cells,natural killer receptors,eomesodermin,cd49d,chronic myeloid leukemia,solid cancers


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