The interaction between natural killer (NK) cells and dendritic cells (DCs) during the innate immune response is thought to greatly impact the quality and strength of the subsequent antigen-specific adaptive immune response. Mechanisms whereby NK cell-DC (NK-DC) crosstalk occurs include reciprocal enhancement of cellular activation and maturation as well as NK cell-mediated elimination of immature DCs (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 have been found to be 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 show here that secretion of IFN-g, a potent inducer of DC differentiation, ??is significantly impaired when NK cells are exposed to autologous mDCs generated from viremic, but not aviremic, HIV-1 infected individuals. Moreover, it was recently demonstrated that the ability to promote DC maturation was essentially confined to NK cells expressing a KIRneg/NKG2Adull/NKp30pos phenotype. We reported that freshly purified NK cells from HIV-1 viremic individuals expressed increased levels of KIRs, while expression of NKG2A and NKp30 was extremely low or absent, particularly among the CD56neg NK cells, a subset present at very low frequencies in both aviremic HIV-1 infected patients and healthy donors. Given the association of these defects with the viremic state, our data suggest that HIV-1, directly or indirectly, interferes with the maturation process of DCs. In fact, despite the expression of cell surface markers associated with a mature phenotype, we found that mDCs derived from viremic patients exhibited several functional defects that could potentially impair the mDC-mediated activation of NK cells. Among these dysfunctional activities, we found that autologous mDCs generated from viremic HIV-1 infected subjects clearly exhibited a markedly impaired capacity to induce both NK cell proliferation and NK cell secretion of IFN-g?. IL-12 is an important cytokine for the activation and proliferation of NK cells. Thus, the reduced IL-12 production by mDCs generated from viremic HIV-1 infected individuals, as demonstrated in this study, may partially account for their defective priming of NK cells. Impairments in the early steps of DC-NK cell crosstalk result in a defect in the ability to limit HIV-1 spread at sites of tissue infection or in secondary lymphoid organs. The lower secretion of IL-10, an HIV-1 inhibitory cytokine in most systems, by mDCs as well as the reduced cytolytic activity of NK cells from HIV-1 infected viremic patients may impair inhibition of HIV-1 replication in the peripheral tissues. Furthermore, it has been shown that IL-10 inhibits the expression of DC co-stimulatory molecules, and, therefore, the weak production of IL-10 by mDCs generated from viremic HIV-1 infected individuals might in part contribute to the mature phenotype of the markedly dysfunctional mDCs. A unique and perhaps more important mechanism through which NK cells are thought to impact the quality of the DCs undergoing maturation in response to antigen uptake is by killing iDCs that failed their maturation program. A recent study showed that DCs generated from viremic HIV-1 infected patients can escape lysis by autologous NK cells, but the underlying cause(s) of this escape have not been identified. In the present study, we delineate the cellular mechanisms that account for impaired NK cell-mediated lysis of autologous iDCs and show that this phenomenon is restricted to those HIV-1-infected individuals with persistent high viremia. Our data demonstrate that the markedly impaired expression/secretion and function of NKp30 and TRAIL largely account for the highly defective NK cell mediated lysis of autologous iDCs generated from viremic HIV-1 infected subjects. Moreover, we show that, within this study group, the high expansion of CD56neg NK cells expressing the unusual KIRpos/NKG2Aneg/NKp30neg/TRAILneg phenotype, a subset present at very low frequencies in either aviremic HIV-1 infected patients or healthy donors, likely explains why this defective elimination of autologous iDCs by NK cells is confined to HIV-1 positive viremic patients. This NK-DC crosstalk represents the proposed mechanism by which the innate immunity is able to prime an effective adaptive immune response in secondary lymphoid organs. The highly defective bidirectional NK-DC crosstalk in chronically HIV-1-infected viremic individuals compared with HIV-1 aviremic patients and uninfected control subjects likely contributes, in the context of HIV-1 pathogenesis, to the escape of virus from a coordinated innate and adaptive immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000958-02
Application #
7313454
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2006
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Fogli, Manuela; Mavilio, Domenico; Brunetta, Enrico et al. (2008) Lysis of endogenously infected CD4+ T cell blasts by rIL-2 activated autologous natural killer cells from HIV-infected viremic individuals. PLoS Pathog 4:e1000101
Ward, Jeffrey; Bonaparte, Matthew; Sacks, Jennifer et al. (2007) HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts. Blood 110:1207-14
Mavilio, Domenico; Lombardo, Gabriella; Kinter, Audrey et al. (2006) Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection. J Exp Med 203:2339-50
Fauci, Anthony S; Mavilio, Domenico; Kottilil, Shyam (2005) NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol 5:835-43
Mavilio, Domenico; Lombardo, Gabriella; Benjamin, Janet et al. (2005) Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci U S A 102:2886-91
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