NK-DC crosstalk occurs during reciprocal enhancement of cellular activation and maturation as well as NK cell-mediated elimination of iDCs. The first contact between immature iDCs and antigens occurs in peripheral tissue at sites of inflammation where iDCs are recruited from the bloodstream, driven by cytokine and chemokine signals produced by resident DCs and other cell types. After antigen uptake, iDCs undergo a maturation process that allows the resulting mature DCs (mDCs) to migrate to secondary lymphoid tissues where they prime an antigen-specific T cell response. NK cells are extremely important in optimizing the differentiation of mDCs in order to prime an effective antigen-specific adaptive immune response. This process requires both NK-DC interactions and NK cell secretion of specific cytokines. Under physiological conditions, the DC maturation program is induced directly by microbial signals as well as by activated NK cells performing a regulatory role. ? ? We described a markedly dysfunctional maturation of DCs that manifest the phenotypic changes of maturity based on the expression of several co-stimulatory markers and MHC class I and II molecules in HIV-1 viremic individuals. These abnormally matured DCs were significantly impaired in their ability to secrete IL-10 and IL-12 and to prime the proliferation of neighboring autologous NK cells. This resulted in an inability of NK cells to secrete adequate amounts of IFN-g, which is pivotal for maturation of DCs. Under physiological conditions, maturation of DCs is induced directly by microbial signals as well as by activated KIRneg/NKG2Adim/NKp30pos NK cells performing a regulatory role. In this regard, the lower secretion of IFN-g by NK cells that mostly express a KIRpos/NKG2Aneg/NKp30low-neg phenotype among HIV-1 infected viremic individuals negatively interferes with the NK cell-mediated editing process in the maturation of DCs. Moreover, NK cells purified from HIV-1 infected viremic individuals also were markedly impaired in their ability to eliminate autologous iDCs when compared to that of aviremic individuals. This phenomenon is largely due to the high frequency of a dysfunctional CD56neg NK cell subset, whose surface expression/secretion and function of NKp30 and TNF-related apoptosis-inducing ligand (TRAIL) molecules (receptors that are responsible for elimination of iDCs) are either extremely low or absent. The abnormal NK cell-mediated editing or elimination of iDCs along with the inability of DCs to prime NK cells in HIV viremic individuals demonstrate yet another mechanism by which HIV-1 negatively impacts and thus circumvents innate and adaptive immune responses? ? NK cell cytolytic machinery is modulated by a delicate balance between opposing signals delivered by two heterogeneous families of inhibitory and activating NK cell receptors. Under physiological conditions, cytotoxicity against normal autologous cells is blocked by the specific recognition of different MHC-I alleles by inhibitory NK cell receptors (iNKRs). Tolerance to self and determination of cytolytic activity are achieved through the involvement of iNKR-MHC-I interactions to ensure self-recognition. Diminution or absence of expression of HLA-I molecules on a cell surface following viral infection or tumor transformation results in the reduced engagement of iNKRs and allows activating NK receptors and co-receptors to trigger NK cell-mediated cytolysis. In this regard, little is known about the ability of NK cells from HIV-1 infected individuals to eliminate infected autologous CD4+ T cells. ? ? We show that in vitro HIV-1 infection down-modulated HLA-A and B alleles on endogenously infected CD4+ T cell-derived blasts, while the expression of HLA-C and HLA-E molecules was conserved. The selective down-regulation of these MHC-I molecules rendered endogenously infected CD4+ T cell-derived blasts susceptible to NK cell-mediated killing. In fact, although the high surface levels of HLA-C and -E protected endogenously infected CD4+ T cell-derived blasts from the cytolysis exerted by NK cells expressing iNKRs specific for these conserved alleles of MHC-I, this is not the case for NK cells that express iNKRs specific for HLA-A and B. In this regard, we show also that the degree of NK cell-mediated lysis of infected blasts was significantly higher compared with that of uninfected blasts. ? ? Masking experiments highlighted the important role of the selective down-modulation of HLA-I molecules, because only the complete blocking of all MHC-I alleles rendered infected and uninfected CD4+ T cell-derived blasts equally susceptible to NK cell-mediated lysis. The engagement of activating NK cell receptors should be able to trigger cytolytic activity in NK cells expressing iNKRs specific for HLA-A and -B and lacking iNKRs for HLA-C and-E. NK cell-mediated killing of endogenously infected CD4-derived T cell blasts was found to be mainly NKG2D-dependent. These results are consistent with the highly conserved expression of NKG2D on NK cells from HIV-1 infected individuals and with the relatively high percentages of endogenously infected CD4+ T cell-derived blasts expressing NKG2D ligands. ? ? In contrast, the contribution of NKp46 and NKp30 to NK cell-mediated killing of autologous infected blasts was generally very low in most HIV-1 infected viremic patients analyzed in the present study. The fact that the NCR ligands were expressed at very low levels on endogenously HIV-1 infected blasts was in line with the lack of engagement of these three activating receptors with their ligands. Moreover, the significantly lower NK cell surface expression of NKp46 and NKp30, compared to that of healthy donors, correlated with the degree of NK cell-mediated lysis of autologous HIV-1 infected blasts in infected viremic patients. Furthermore, we previously reported that chronic HIV-1 viremia is associated with the presence of a highly dysfunctional iNKR+/NKG2A-/CD56- NK cell subset expressing almost undetectable levels of NKp46 and NKp30. The frequency of this pathologic CD56- population inversely correlated with the ability of NK cells to kill autologous HIV-1 infected blasts. These results confirmed that the aberrant expression and function of NKp46 and NKp30 in this overrepresented CD56- NK cell population likely interfere with NK cell-mediated killing of autologous HIV-1 infected CD4+ T cell-derived blasts.? ? In conclusion, the present study demonstrates that several factors including the selective down-modulation of HLA-I molecules on naturally infected cells, the differential engagement of activating NK cell receptors with their ligands and the inherent functional abnormalities of the pathologic CD56- NK cell subsets influenced the NK cell-mediated cytolysis of endogenously infected CD4+ T cells.
