Immunosuppression following infection with HIV-1 predisposes patients to a myriad of opportunistic pathogens, one of the most important of which is Mtb . Granulysin, expressed by NK cells and CTL, exhibits potent antimicrobial activity against Mtb and several other opportunistic pathogens associated with HIV-1 infection. The immune signals that promote granulysin expression in human CTL are not fully understood. Using primary human CD8 + T cells, in this study, we identify IL-21 as a strong inducer of granulysin, demonstrate that IL-21 and IL-15 activate granulysin expression within CD8 + CD45RO + T cells, and establish a role for Jak/STAT signaling in the regulation of granulysin within CD8 + T cells. We show that infection of PBMC from healthy donors in vitro with HIV-1 suppresses granulysin expression by CD8 + T cells, concomitant with reduced p-STAT3 and p-STAT5, following activation with IL-15 and IL-21. Of note, simultaneous signaling through IL-15 and IL-21 could partially overcome the immunosuppressive effects of HIV-1 on granulysin expression by CD8 + T cells. These results suggest that HIV-1 infection of PBMC may reduce the antimicrobial profile of activated CD8 + T cells by disrupting signaling events that are critical for the induction of granulysin. Understanding the effects of HIV-1 on CD8 + T cell activation is essential to understanding the physiological basis for inadequate cytotoxic lymphocyte activity in HIV + patients and for informed guidance of cytokine-based therapy to restore T cell function.
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Induction of granulysin in CD8+ T cells by IL-21 and IL-15 is suppressed by human immunodeficiency virus-1
Hogg, A. E.; Bowick, G. C.; Herzog, N. K.; Cloyd, M. W.; Endsley, J. J.
Follow Journal of Leukocyte Biology
, Volume 86 (5): 1191
Fed of American Socs for Experimental Biology – Nov 1, 2009
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