P2X7 Receptor Inhibition Improves CD34 T-Cell Differentiation in HIV-Infected Immunological Nonresponders on c-ART

PLoS Pathogens

Inna Menkova-Garnier¹  Pascaline Tisserand¹  Clarisse Benne¹  Hakim Hocini²  Jean-Daniel Lelièvre²  Constance Delaugerre²  Emile Foucat³  Laure Bourdery³  Yves Lévy³ 

[1] INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France;Université Paris Est Créteil, Faculté de Médecine, Créteil, France;Vaccine Research Institute, Créteil, France

关键词: T cells;    Cell differentiation;    Inflammation;    B cells;    Immune activation;    Blood;    Blood plasma;    Cytotoxic T cells;   

DOI  :  10.1371/journal.ppat.1005571

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Peripheral CD4+ T-cell levels are not fully restored in a significant proportion of HIV+ individuals displaying long-term viral suppression on c-ART. These immunological nonresponders (INRs) have a higher risk of developing AIDS and non-AIDS events and a lower life expectancy than the general population, but the underlying mechanisms are not fully understood. We used an in vitro system to analyze the T- and B-cell potential of CD34+ hematopoietic progenitor cells. Comparisons of INRs with matched HIV+ patients with high CD4+ T-cell counts (immune responders (IRs)) revealed an impairment of the generation of T-cell progenitors, but not of B-cell progenitors, in INRs. This impairment resulted in the presence of smaller numbers of recent thymic emigrants (RTE) in the blood and lower peripheral CD4+ T-cell counts. We investigated the molecular pathways involved in lymphopoiesis, focusing particularly on T-cell fate specification (Notch pathway), survival (IL7R-IL7 axis) and death (Fas, P2X7, CD39/CD73). P2X7 expression was abnormally strong and there was no CD73 mRNA in the CD34+ cells of INRs, highlighting a role for the ATP pathway. This was confirmed by the demonstration that in vitro inhibition of the P2X7-mediated pathway restored the T-cell potential of CD34+ cells from INRs. Moreover, transcriptomic analysis revealed major differences in cell survival and death pathways between CD34+ cells from INRs and those from IRs. These findings pave the way for the use of complementary immunotherapies, such as P2X7 antagonists, to restore T-cell lymphopoiesis in INRs.

【 授权许可】

CC BY