Mechanisms of NK cell recognition of SIV-infected CD4+ T cells
Final Report Abstract
NK cells are innate immune cells able to recognize and lyse virus-infected cells without prior sensitization. Whereas the fundamental importance of NK cell contributions to the host defense against viral infections, such as HIV in human and SIV in rhesus macaques, have been well established, many mechanistic questions of how the interaction is mediated remain to be answered. In particular, virtually nothing is known about the receptors, which enable rhesus macaque NK cells to recognize SIV-infected CD4+ T cells. During my postdoctoral work in the Johnson lab at Harvard Medical School, I could show that ligands for the activating NK cell receptor NKG2D are not detectable on SIV-infected CD4+ T cells. These data suggest that NKG2D is unlikely to play a major role in the recognition of SIV-infected cells by rhesus NK cells. I furthermore established and validated a novel approach to quantitate the virus-suppressive capacity of macaque effector cells, including CD8+ T cells and NK cells. I could show that the virus-inhibiting potential of CD8+ T cells strongly correlates with the ability of these cells to degranulate upon stimulation with Gag and Env peptides. Given that IFN-γ remains one of the most frequently measured immune responses to examine the magnitude of immune responses against viruses, my results strongly suggest that CD107a is a superior marker as it represents a correlate with a more physiologically relevant function. I also established a highly parallel RT-PCR approach as a novel, powerful tool to study rhesus macaque NK cells. Using these tools, we addressed the question whether macaque NK cells are able to recognize virus-infected cells. Notably, there was a great animal-to-animal variation in the ability of the NK cells to specifically react to SIV-infected cells. This work could only be partially completed. Thus, the mechanism of the recognition of SIV-infected cells by macaque NK cells still remains to be identified. In further collaborative research efforts with the Meyer-Olson lab at the Medical School Hannover (MHH), I was able to show that two NK parameters represent robust correlates with the immune and clinical state of HIV-infected patients. I was able to demonstrate significant correlations of the loss of CD56bright NK cells with HIV viral loads and loss of CD4+ T cell counts. In addition, I identified a thus far not well-studied CD8+ NK cell population in HIV patients, which was associated with delayed disease progression to AIDS. These CD8+ NK cells were phenotypically very similar to CD8-devoid NK cells but remarkably exhibited a more functional profile. These results therefore suggest, that NK cell-derived innate immune markers exist, which strongly correlate with clinical disease parameters in HIV infection. Further studies are warranted to evaluate if and how these cells can play an active role in the host defense against viral infections as suggested by their highly functional state.
Publications
- Loss of CCR7 expression on CD56bright NK cells is associated with a CD56dimC16+ NK cell-like phenotype and correlates with HIV viral load. PLoS One. 2012;7(9):e44820
Hong HS, Ahmad F, Eberhard JM, Bhatnagar N, Bollmann BA, Keudel P, Ballmaier M, Zielinska-Skowronek M, Schmidt RE, Meyer-Olson D
(See online at https://doi.org/10.1371/journal.pone.0044820) - No monkey business: why studying NK cells in non-human primates pays off. Front Immunol. 2013 Feb 18;4:32
Hong HS, Rajakumar PA, Billingsley JM, Reeves RK, Johnson RP
