Abstract
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-gamma 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.
Highlights
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The absence of Th2 cell development was controlled by CD8 T cells, because immunization of CD8-deficient parental strains with CB6 F1 APCs induced allospecific CD4 T cells producing a large amount of Th2-type cytokines [10]
We initially thought of using CB6 F1 APCs to prime alloreactive host CD4 T cells on the assumption that F1 APCs expressed, in addition to allogeneic MHC products, self MHC class I molecules that bind to inhibitory receptors on host NK cells, thereby silencing inhibitory receptor-bearing cells
Summary
DC, dendritic cell; 2m, 2-microglobulin; BM-DC, bone marrow-derived DC; LNC, lymph node cell; SC, spleen cell; WT, wild type. CONTROL OF ALLOSPECIFIC Th CELL RESPONSES BY NK CELLS levels of IL-4 and IL-10 similar to the responses observed in 2microglobulin (2m) and CD8 double knockout mice where NK cell activity is impaired [11,12,13]. Grafting CD8-deficient mice with semiallogeneic skin induced marked allospecific Th2 cell priming; whereas rejection of allogeneic grafts was associated with the selective development of Th1 cells. In this latter combination, turning NK cells off resulted in a skewing of the alloreactive CD4 T cell response to the Th2 pathway without affecting the kinetics of skin graft rejection. Our data demonstrate that recognition of donor APCs by host NK cells strongly affects the magnitude of allospecific Th cell responses as well as their cytokine secretion profiles in various donor/recipient strain combinations
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