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      Naive tumor-specific CD4 + T cells differentiated in vivo eradicate established melanoma

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          Abstract

          In vitro differentiated CD8 + T cells have been the primary focus of immunotherapy of cancer with little focus on CD4 + T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4 + T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8 +, B, natural killer (NK), and NKT cells. Proper activation of CD4 + T cells in vivo was important for tumor clearance, as naive tumor-specific CD4 + T cells could not completely treat tumor in lymphopenic common gamma chain (γ c)–deficient hosts. γ c signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4 + T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4 + T cells.

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          Taking dendritic cells into medicine.

          Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.
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            CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes.

            A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (T(H)) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on T(H) cells. A clearer understanding of the contribution of T(H) cells to CTL development has been hampered by the fact that most T(H)-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T(H)-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T(H)-dependent and T(H)-independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T(H) cells during, but not after, priming. Our results demonstrate that T-cell help is 'programmed' into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.
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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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                Author and article information

                Journal
                J Exp Med
                J. Exp. Med
                jem
                The Journal of Experimental Medicine
                The Rockefeller University Press
                0022-1007
                1540-9538
                15 March 2010
                : 207
                : 3
                : 651-667
                Affiliations
                [1 ]Program in Molecular Microbiology and Immunology , [2 ]Laboratory of Immunology and Cancer Immunotherapy, Department of Pathology , and [3 ]Department of Epidemiology and Preventative Medicine, University of Maryland School of Medicine, Baltimore, MD 21201
                [4 ]Tumor Immunology and Immunotherapy Program and [5 ]Program in Oncology, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD 21201
                [6 ]Laboratory of Cellular and Molecular Immunology, National Institutes of Allergy and Infectious Disease, Bethesda, MD 20892
                [7 ]Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287
                [8 ]Surgery Branch, Center for Cancer Research, Bethesda, MD 20892
                Author notes
                CORRESPONDENCE Paul Andrew Antony: pantony@ 123456som.umaryland.edu
                Article
                20091921
                10.1084/jem.20091921
                2839147
                20156973
                65776c3c-7894-42bc-8423-10a5e842c2c2
                © 2010 Xie et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 3 September 2009
                : 19 January 2010
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                Medicine
                Medicine

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