NLRP3 and NLRP1/CARD8 pathways differently contribute to pyroptosis of CD8+ T cells of ART-treated HIV patients

Abstract

HIV-infected (HIV) patients exhibit immune dysregulation independently of antiretroviral therapy. The inflammasome, a cytosolic complex responsible for cleavage of the inflammatory cytokines IL -1{beta} and IL -18 and pyroptosis, is highly activated in peripheral blood mononuclear cells of HIV patients, suggesting its involvement in leukocyte dysfunction. While monocytes, B cells, and CD4+ T cells have been studied, little is known about CD8+ T lymphocytes. Therefore, we proposed to characterize the inflammasome activation in these cells, both the NLRP3 and NLRP1/CARD8 pathways, which are partially described in T cells. CD8+ T lymphocytes from non-HIV healthy donors (HD) and HIV patients were analyzed ex vivo and stimulated in vitro with known activators of NLRP3 (-CD3/-CD28), NLRP1 and CARD8 (DPP9 inhibitor ValboroPro, VbP) to assess inflammasome activation. HIV CD8+ T cells present a constitutively activated caspase-1 which positively correlates with the cell activation state. HIV CD8+ T cells were more activated and more resistant to VbP-induced pyroptosis than HD. On the other way, HIV CD8+ T lymphocytes showed higher pyroptosis in response to -CD3/-CD28. These findings suggest that the NLRP3 pathway is significantly dysregulated in those patients, and TCR stimulation may result in cell loss. At the same time, being HIV CD8+ T cells constitutively activated, other inflammasome pathways, such as NLRP1 or CARD8, present a delayed activation.