CD8+ T-cell–mediated killing of donor dendritic cells prevents alloreactive T helper type-2 responses in vivo

S Laffont, JD Coudert, L Garidou, L Delpy… - Blood, 2006 - ashpublications.org
S Laffont, JD Coudert, L Garidou, L Delpy, A Wiedemann, C Demur, C Coureau, JC Guéry
Blood, 2006ashpublications.org
Accumulating evidence indicates that, in absence of CD8+ T-cell activation, CD4+ T-cell–
mediated allograft rejection is associated with a dominant Th2-cell response and eosinophil
infiltrates. In this study, we analyzed the mechanisms by which CD8+ T cells regulate
alloreactive CD4+ T-cell priming and differentiation into interleukin 4 (IL-4)–producing cells.
We showed that interferon γ (IFN-γ) production by CD8+ T cells was dispensable for the
inhibition of Th2-cell development, as well as tissue eosinophilia and type 2 cytokine …
Abstract
Accumulating evidence indicates that, in absence of CD8+ T-cell activation, CD4+ T-cell–mediated allograft rejection is associated with a dominant Th2-cell response and eosinophil infiltrates. In this study, we analyzed the mechanisms by which CD8+ T cells regulate alloreactive CD4+ T-cell priming and differentiation into interleukin 4 (IL-4)–producing cells. We showed that interferon γ (IFN-γ) production by CD8+ T cells was dispensable for the inhibition of Th2-cell development, as well as tissue eosinophilia and type 2 cytokine production in the rejected grafts. Since we noticed that CD8+ T cells not only suppressed Th2 differentiation, but also down-modulated the overall priming of alloreactive CD4+ T cells, we evaluated whether CD8+ T cells act by limiting the accumulation of donor-derived dendritic cells (DCs) in lymph nodes. We found that indeed, alloreactive CD8+ T cells rapidly eliminated allogeneic DCs from T-cell areas of draining lymph nodes, through a perforin-dependent mechanism. Thus, our data demonstrate that cytotoxic T lymphocyte (CTL)–mediated clearance of allogeneic DCs is a negative feedback mechanism that limits the duration of alloantigen presentation in draining lymph nodes, thereby modulating the amplitude and polarization of the primary alloreactive CD4+ T-cell responses.
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