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. 2022 Sep 29:10:961021.
doi: 10.3389/fcell.2022.961021. eCollection 2022.

An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposi's sarcoma under ART

Genevieve T Clutton  1 , Ann Marie K Weideman  2   3 , Nilu P Goonetilleke  1   4 , Toby Maurer  5
Affiliations

An expanded population of CD8dim T cells with features of mitochondrial dysfunction and senescence is associated with persistent HIV-associated Kaposi's sarcoma under ART

Genevieve T Clutton et al. Front Cell Dev Biol. .

Abstract

HIV-associated Kaposi's sarcoma (KS), which is caused by Kaposi's sarcoma-associated herpesvirus, usually arises in the context of uncontrolled HIV replication and immunosuppression. However, disease occasionally occurs in individuals with durable HIV viral suppression and CD4 T cell recovery under antiretroviral therapy (ART). The underlying mechanisms associated with this phenomenon are unclear. Suppression of viral infections can be mediated by CD8 T cells, which detect infected cells via their T cell receptor and the CD8 coreceptor. However, CD8 T cells exhibit signs of functional exhaustion in untreated HIV infection that may not be fully reversed under ART. To investigate whether KS under ART was associated with phenotypic and functional perturbations of CD8 T cells, we performed a cross-sectional study comparing HIV-infected individuals with persistent KS under effective ART (HIV+ KS+) to HIV-infected individuals receiving effective ART with no documented history of KS (HIV+ KSneg). A subset of T cells with low cell surface expression of CD8 ("CD8dim T cells") was expanded in HIV+ KS+ compared with HIV+ KSneg participants. Relative to CD8bright T cells, CD8dim T cells exhibited signs of senescence (CD57) and mitochondrial alterations (PGC-1α, MitoTracker) ex vivo. Mitochondrial activity (MitoTracker) was also reduced in proliferating CD8dim T cells. These findings indicate that an expanded CD8dim T cell population displaying features of senescence and mitochondrial dysfunction is associated with KS disease under ART. CD8 coreceptor down-modulation may be symptomatic of ongoing disease.

Keywords: CD8 coreceptor; HIV; KSHV; Kaposi’s sarcoma; T cells; metabolism; mitochondria; senescence.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
CD8dim T cells with low mitochondrial activity are expanded in individuals with persistent KS. (A) Representative plots showing CD8bright and CD8dim T cells in a HIV+ KSneg and a HIV+ KS+ participant. (B) The frequency of CD8dim T cells (as a percentage of total CD8 T cells) is significantly elevated in HIV+ individuals with persistent KS under ART (KS+; n = 7) compared with the KSneg group (n = 8) (difference of medians = 12.28%; Mann-Whitney test). (C) A significantly higher percentage of CD8dim T cells express CD57 compared with CD8bright T cells (median of differences = 8%; Wilcoxon signed-rank test). (D) A significantly higher percentage of CD8dim T cells express Eomes compared with CD8bright T cells (median of differences = 13.5%; Wilcoxon signed-rank test). (E) Expression of the mitochondrial master regulator PGC-1α is significantly reduced in CD8dim T cells (median of differences = −789 MFI; Wilcoxon signed-rank test). (F) The frequency of MitoTracker Deep Red high cells is significantly lower for CD8dim T cells compared with CD8bright T cells (median of differences = −8.99%; Wilcoxon signed-rank test). Gray open squares, HIV+ KS+ participants; black circles, HIV+ KSneg participants.
FIGURE 2
FIGURE 2
Mitochondrial activity is reduced in CD8dim proliferating cells. (A) Histograms showing CFSE dilution in unstimulated and PHA-stimulated CD8 T cells. (B) MitoTracker Deep Red (MTDR) fluorescence in PHA-stimulated proliferating (CFSElow) cells. A significantly higher percentage of proliferating (CFSElow) CD8 T cells are MTDRhigh compared with non-proliferating (CFSEhigh) CD8 T cells, indicating that proliferating cells have higher mitochondrial activity (n = 10; median of differences = 23.25%; Wilcoxon signed-rank test). (C) Positive association between mitochondrial activity (% MTDRhigh) of all CD8 T cells in the culture and the proliferation index of proliferating cells in response to PHA stimulation (Spearman correlation). (D) Negative association between mitochondrial activity and the frequency of CD8dim T cells following stimulation with PHA (Spearman correlation). (E) The frequency of MTDRhigh cells, comparing CD8bright and CD8dim proliferating (CFSElow) cells. CD8dim proliferating cells are significantly less likely to be MTDRhigh, indicating lower mitochondrial activity (median of differences = −23.35%; Wilcoxon signed-rank test). (F) Proliferation index of PHA-stimulated CD8 T cells versus the frequency of CD8dim T cells in the culture (Spearman correlation). Gray open squares, HIV+ KS+ participants; black circles, HIV+ KSneg participants.
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