The Rapid Induction of HLA-E Is Essential for the Survival of Antigen-Activated Naive CD4 T Cells from Attack by NK Cells

Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(10):6031-40. DOI: 10.4049/jimmunol.1000176
Source: PubMed


Increasing evidence shows that NK cells regulate adaptive immunity, but the underlying mechanisms are not well understood. In this study, we show that activated human NK cells suppress autologous naive CD4 T cell proliferation in response to allogeneic dendritic cells (DCs) by selectively killing Ag-activated T cells. Naive CD4 T cells, which were initially resistant to NK cell-mediated cytotoxicity, became substantially susceptible to NK cells within a day after priming with DCs. Ag-activated T cells showed various degrees of susceptibility to NK cells. After 1 d of priming with LPS-matured DCs, T cells were less susceptible to NK cells than were T cells primed with TNF-α-matured DCs. Subsequently at day 3, Ag-activated T cells regained resistance to NK cells. The level of HLA-E expression on Ag-activated T cells was closely correlated with resistance to NK cells. HLA-E was highly expressed at day 1 by T cells primed with LPS-matured DCs but not by T cells primed with TNF-α-matured DCs. An Ab blockade revealed a critical role for the HLA-E-NKG2A interaction in the protection of Ag-activated T cells from NK cells. Collectively, this study demonstrates that NK cells impact adaptive immunity through the finely controlled kinetics of HLA-E expression on T cells. Thus, HLA-E may be a new target for immunoregulation.

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    • "Interestingly, resting DCs and microglia are susceptible to NK cell-mediated cytotoxicity [57], [58], whereas activation of these cells upregulates MHC class I molecules and confers resistance to lysis [25]. On the contrary, resting monocytes, monocyte-derived macrophages and T cells are protected from NK cell-mediated cytotoxicity, but upon activation these cells upregulate NKG2D ligands and become susceptible to NK cell lysis [9], [18], [25], [59], [60]. We found that resting CD4+ T cells expressed much lower levels of all MHC class I molecules compared to activated CD4+ T cells (Fig. S3), yet resting CD4+ T cells were not susceptible to NK cell-mediated lysis, and blocking with an anti-HLA class I antibody did not result in NK cell degranulation. "
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