Editors' ChoiceInnate Immunity

How HIV Reduces Antifungal Immunity

Science Signaling  22 Oct 2013:
Vol. 6, Issue 298, pp. ec253
DOI: 10.1126/scisignal.2004826

Natural killer (NK) cells are cells of the innate immune system and kill fungi by releasing perforin, a pore-forming protein that lyses target cells. The mechanism by which NK cells detect fungal invaders, however, has not been identified. Li et al. report that the NK receptor NKp30, previously demonstrated to mediate NK cell cytotoxicity against cancer cells, mediates recognition of the fungal pathogens Cryptococcus neoformans and Candida albicans. NKp30 was present on the surface of primary human NK cells and YT cells, which are cultured human leukemic NK cells, and localized to the immunological synapse formed between YT cells and C. neoformans. A monoclonal antibody that bound to NKp30 inhibited C. neoformans and C. albicans killing by YT cells, as did knockdown of NKp30. The monoclonal antibody also competed with fungal cell wall components and C. neoformans for binding to YT cells and prevented activation of signaling pathways involved in the YT cell response to C. neoformans. The monoclonal antibody also reduced the release of perforin from YT cells and primary human NK cells in response to C. neoformans. C. neoformans and C. albicans cause opportunistic infections in immune-suppressed individuals, particularly those infected with the human immunodeficiency virus (HIV), which causes reduced NK cell function (although the virus infects a different cell type of the immune system). NK cells from HIV-infected patients showed reduced abundance of NKp30, reduced C. neoformans killing, and less perforin release compared to NK cells from healthy HIV-negative individuals. Treatment with interleukin-12 (IL-12), which improves the function of NK cells isolated from HIV patients, increased the abundance of NKp30 in NK cells derived from HIV-infected patients but had no effect on NKp30 abundance in NK cells from HIV-negative individuals. IL-12 treatment increased the ability of HIV patient–derived NK cells to kill C. neoformans, and the monoclonal antibody that recognizes NKp30 inhibited this effect. These findings identify a receptor responsible for recognition and killing of fungal pathogens by NK cells and explain the reduced antifungal activity exhibited by NK cells from HIV-infected individuals.

S. S. Li, S. K. Kyei, M. Timm-McCann, H. Ogbomo, G. J. Jones, M. Shi, R. F. Xiang, P. Oykhman, S. M. Huston, A. Islam, M. J. Gill, S. M. Robbins, C. H. Mody, The NK receptor NKp30 mediates direct fungal recognition and killing and is diminished in NK cells from HIV-infected patients. Cell Host Microbe 14, 387–397 (2013). [PubMed]