Browsing by Subject "CD4+ T Cells"

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    Graft antigen-specific CD4+ T cells require CD154 expression to clonally expand and differentiate to the TH1 phenotype and initiate mTOR dependant intimal hyperplasia in cardiac allografts
    (2009-08) Huddleston, Stephen James MD
    A defined model system was used to address the role of minor histocompatibility antigen-specific CD4+ T cells in cardiac allograft vasculoopathy (CAV). The coronary arteries of vascularized heart grafts from Act-mOVA transgenic mice expressing the model antigen ovalbumin developed CAV in normal recipients and those lacking CD8+ T cells but not in those lacking CD4+ T cells. Furthermore, purified ovalbumin-specific CD4+ T cells from T cell antigen receptor (TCR) transgenic mice caused CAV in ovalbumin-expressing heart grafts in lymphocyte-deficient mice. This model system was used to study the role of CD154 expression, specific T helper subtype cytokine secretion, and the post CD4+ T cell-mediated injury phase of intimal hyperplasia. The graft antigenspecific CD4+ T cells only caused intimal hyperplasia when expressing CD154 and were found in the intima of the affected coronary arteries along with CD40+ cells. These results show that minor histocompatibility antigen-specific CD4+ T cells are required to cause cardiac allograft vasculopathy. They are capable of doing so without contributions from other lymphocytes, and may cause CAV by using CD154 to stimulate other nonlymphoid cells in the intima. The mechanism of CD154-dependant CD4+ T cell mediated CAV is not known. In order to determine the relevant cytokine profile involved in CD4+ T cell mediated CAV, ovalbumin-specific CD4+ T cells were differentiated in vitro into TH1, TH2, and TH17 cells, which produce the prototypic cytokines, IFN-, IL-4, and IL-17, respectively, and transferred into lymphocyte-deficient recipients of ovalbuminexpressing heart grafts. In vitro-generated TH1 and TH17, but not TH2 cells caused CAV. However, naïve ovalbumin-specific CD4+ T cells differentiated only into TH1 cells in vivo in recipients of ovalbumin-expressing heart grafts. Surprisingly, ovalbuminexpressing grafts transplanted into both STAT-4-deficient recipients with defective TH1 subset generation and IFN-y-deficient recipients developed CAV, although to a less severe degree than in wild-type recipients. Furthermore, IFN-y-deficient ovalbuminspecific CD4+ T cells caused CAV similar to normal ovalbumin-specific CD4+ T cells. Thus, minor antigen-specific CD4+ T cells differentiate to the TH1 subset in the presence of heart grafts expressing the relevant antigen, causing CAV in the absence of other lymphocytes. Although IFN-y is involved, it is not the only factor produced by these cells that causes CAV. Whether a single episode of CD4+ T cell mediated injury, as opposed to multiple rejection episodes or ongoing activation, are required for the development of CAV is not known. When CD4+ T cells were depleted after the peak of clonal expansion but before the onset of intimal hyperplasia, CAV still developed in Act-mOVA grafts, suggesting that graft antigen-specific CD4+ T cells are critical for the immune injury phase of CAV but are not required once the graft is injured. Furthermore, the intimal hyperplasia phase of CAV was found to be mTOR dependant. Although graft antigenspecific CD4+ T cells initiate CAV, they are not necessary for progression of CAV.