Lymphocytes T CD4 et immunité anti-tumorale naturelle : impact de la chimiothérapie, émergence de lymphocytes T CD4 cytotoxiques

Abstract : Historically, CD8 positive Cytotoxic T Lymphocytes (CTL) have been associated with an effector immune response, while T cells with a CD4 phenotype where considered helper T cells. More recent data suggest that CD4 positive T cells are also capable of a direct cytotoxic activity. Through a systematic analysis of the IL-2 (CD25) as well as IL-7 (CD127) receptors α on the surface of CD4+ CTL in peripheral blood of patients before during and after treatment we were able to identify a specific CD4+ T cell population devoid of expression for these 2 molecules. These CD4+, CD25-CD127-, T cells only represent 0,2-2% of the total CD4+ pool in peripheral blood of healthy donors, while in the presence of a chronic infectious disease such as HIV or tuberculosis they were increased, representing up to 2-20% of all CD4+ T cells. Similarly, high numbers of CD4+, CD25-CD127-, T cells could be identified in the circulation in patients with metastatic uveal melanoma (muM) or with breast cancer. These chronically stimulated T cells (chCD4) demonstrate a memory effector phenotype (CD45RO+); while the majority shows a terminally differentiated phenotype (CD57+), these T cells all arbore distinct phenotypic characteristics as defined by the absence of expression of CD28 together with the presence of a surface expression of integrin CD11b and of the NK receptor, 2B4. The presence of cytoplasmic granules concentrating granzyme B and perforin, known to be responsible for T cell cytotoxicity, were identified in effector chCD4 while they were absent in conventional CD4+ T cells as well as in Tregs. This cytotoxic potential was demonstrated through redirected cytotoxicity assays that functionally confirm this feature of these chronically activated CD4+ T cells. The secretory cytokine profile showed absent IL-17 levels and a Th1 orientation, asking questions as regards to the lineage of this particular T cell population. Ki67 expression, a marker of cell proliferation, was absent, suggestive of their ability to persist quiescently in patients. However in muM patients we were able to demonstrate a vast oligoclonal increase in chCD4+ T cells, which correlated positively with CD8+ T cells. We were able to detect a high frequency of T cells responding against a specific tumor antigen among these CD8+ T cells. We furthermore studied the effects of chemotherapy on peripheral lymphocyte populations. In breast cancer patients who had been treated with preoperative (neoadjuvant) chemotherapy we detected high levels of effector chCD4 in 17/22 patients. Of particular interest was the fact that this increase through a course of chemotherapy treatment was strongly correlated to the percentage of regression of the original tumor. Together, these results cast new light on the role and function of CD4+ T cells in tumor immunity. Our observations show that CD4+ cytotoxic T lymphocytes do exist and suggest for the first time in human that they may have an important role in response to treatment and in particular in the establishment of a durable protective immune response.
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Isabelle Peguillet. Lymphocytes T CD4 et immunité anti-tumorale naturelle : impact de la chimiothérapie, émergence de lymphocytes T CD4 cytotoxiques. Immunologie. Université René Descartes - Paris V, 2014. Français. ⟨NNT : 2014PA05T034⟩. ⟨tel-01089027⟩

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