Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells

Abstract

What governs the increased apoptosis sensitivity of HIV-specific CD8 ؉ T cells is poorly understood. Here, we examined the involvement of mitochondria in this apoptosis. Remarkably higher mitochondrial mass (MM) was found in HIV-specific compared with CMV-specific CD8 ؉ T cells from HIV ؉ patients and this could not be attributed to their different differentiation status. MM High phenotype characterized those CD8 ؉ T cells from HIV ؉ patients that are sensitive to spontaneous and CD95/Fas-induced apoptosis. CD38 expression did not correlate with high MM, whereas Bcl-2 levels were significantly reduced in both CD38 ؉ and CD38 ؊ HIVspecific CD8 ؉ T cells. Although CD38 ؉ HIV-specific CD8 ؉ T cells were more susceptible to apoptosis, CD38 expression does not explain on its own the selective apoptosis sensitivity of HIV-specific CD8 ؉ T cells, as CD38 ؊ HIV-specific CD8 ؉ T cells were more apoptotic than CD38 ؉ CMV-specific ones. Proapoptotic HIVspecific CD8 ؉ T cells were CD38 ؉ Bcl-2 Low MM High . Copolarization of mitochondria with CD95/Fas capping, very early in CD95/Fas-induced apoptosis of HIV-specific CD8 ؉ T cells, suggests that mitochondria act as an amplification step for this apoptosis. Thus, an extensive mitochondrial network contributes to apoptosis sensitivity of CD8 ؉ T cells and, when this occurs together with reduced levels of Bcl-2 and chronic activation, determines the proapoptotic state of HIV-specific CD8 ؉ T cells. IntroductionCD8 ϩ T-cell response is a critical player for controlling HIV infection and AIDS progression. 1,2 However, HIV-specific CD8 ϩ T cells ultimately fail to control the virus. Various mechanisms related either to HIV-infected cells or to intrinsic defects in CD8 ϩ T cells themselves have been proposed to explain this failure. [3][4][5] Among others, apoptosis of HIV-specific CD8 ϩ T cells has been suggested as a strategy employed by HIV to evade the immune system. 6,7 What governs this apoptosis sensitivity, however, remains to be elucidated.CD8 ϩ T cells from HIV-infected patients are susceptible to spontaneous and CD95/Fas-induced apoptosis. [8][9][10] We recently found HIVspecific CD8 ϩ T cells to be highly sensitive to apoptosis 11 whereas this is not the case for CMV-specific CD8 ϩ T cells from HIV ϩ individuals. 11 This sensitivity is associated with a remarkable down-regulation of Bcl-2 and Bcl-xL antiapoptotic molecules, 12 suggesting a role of mitochondria in this apoptotic process. Several studies have revealed a mitochondrial dysfunction in T cells during HIV infection. 13,14 CD95/ Fas cross-linking initiates a complex signaling process involving CD95/Fas capping and formation of death-inducing signaling complex (DISC), 15,16 ultimately leading to activation of the executor caspase-3 directly by caspase-8 or through mitochondrial-secreted proapoptotic factors. 17 The cross-talk of these 2 pathways in apoptosis of primary T cells, particularly in CD8 ϩ T cells from HIV ϩ patients, is currently unknown. Furthermore, no studies have addressed the role and impact of ...

Autophagy Is Essential for Mitochondrial Clearance in Mature T Lymphocytes

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Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma

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“…The hallmark of the infection in disease-susceptible species is the progressive decline of the CD4 ϩ T-cell population. CD8 ϩ T cells also show increased sensitivity to HIV-mediated apoptosis (8,12,13,22,35,39), but this population remains more stable during the course of the infection in vivo. Why CD4 ϩ T cells are progressively lost in infected humans and rhesus macaques (RM) yet remain stable in chimpanzees, sooty mangabeys (SM), and African green monkeys (AGM) is not well understood.…”