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Institut National de la Santé et de la Recherche Médicale Unité 563, Centre de Physiopathologie de Toulouse Purpan, Institut Claude de Préval, Hôpital Purpan, Toulouse, France
Although much progress has been made in understanding the role of
NK cells in bone marrow transplantation, little is known about their
function in CD4 T cell-mediated allograft rejection. We have previously
shown that in the absence of CD8 T lymphocyte priming, the in vivo
default development pathway of alloreactive CD4 T cells was strongly
biased toward Th2 phenotype acquisition. In this study, we investigate
the impact of NK cells on the activation and differentiation of
alloreactive CD4 T cells in various donor/recipient combinations. Our
data demonstrate that defective inhibition of host NK cells by donor
APCs including dendritic cells (DCs) results in diminished allospecific
Th cell responses associated with the development of effector Th cells
producing IFN-
rather than type 2 cytokines. Turning host NK cells
off was sufficient to restore strong alloreactive CD4 T cell priming
and Th2 cell development. Similar results were obtained by analyzing
the effect of NK cell activation on CD4 T cell responses to skin
allografts. However, despite the dramatic effect of NK cells on
alloreactive Th1/Th2 cell development, the kinetics of skin graft
rejection were not affected. Thus, Th2 differentiation is a major
pathway of alloreactive CD4 T cell development during solid organ
transplant rejection, as long as host NK and CD8 T cells are not
activated. We propose the hypothesis that MHC class I-driven
interactions between donor DCs and host NK cells or CD8 T cells might
result in DC-carried signals controlling the dynamics of alloreactive
CD4 T cell priming and polarization.
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