Abstract
Chronic T cell activation and accelerated immune senescence are hallmarks of HIV infection, which may contribute to the increased risk of cardiometabolic diseases in people living with HIV (PLWH). T lymphocytes play a central role in modulating adipose tissue inflammation and, by extension, adipocyte energy storage and release. Here, we assessed the CD4+ and CD8+ T cell profiles in the subcutaneous adipose tissue (SAT) and blood of non-diabetic (n = 9; fasting blood glucose [FBG] < 100 mg/dL), pre-diabetic (n = 8; FBG = 100–125 mg/dL) and diabetic (n = 9; FBG ≥ 126 mg/dL) PLWH, in addition to non- and pre-diabetic, HIV-negative controls (n = 8). SAT was collected by liposuction and T cells were extracted by collagenase digestion. The proportion of naïve (TNai) CD45RO−CCR7+, effector memory (TEM) CD45RO+CCR7−, central memory (TCM) CD45RO+CCR7+, and effector memory revertant RA+(TEMRA) CD45RO−CCR7− CD4+ and CD8+ T cells were measured by flow cytometry. CD4+ and CD8+ TEM and TEMRA were significantly enriched in SAT of PLWH compared to blood. The proportions of SAT CD4+ and CD8+ memory subsets were similar across metabolic status categories in the PLWH, but CD4+ T cell expression of the CD69 early-activation and tissue residence marker, particularly on TEM cells, increased with progressive glucose intolerance. Use of t-distributed Stochastic Neighbor Embedding (t-SNE) identified a separate group of predominantly CD69lo TEM and TEMRA cells co-expressing CD57, CX3CR1, and GPR56, which were significantly greater in diabetics compared to non-diabetics. Expression of the CX3CR1 and GPR56 markers indicate these TEM and TEMRA cells may have anti-viral specificity. Compared to HIV-negative controls, SAT from PLWH had an increased CD8:CD4 ratio, but the distribution of CD4+ and CD8+ memory subsets was similar irrespective of HIV status. Finally, whole adipose tissue from PLWH had significantly higher expression of TLR2, TLR8, and multiple chemokines potentially relevant to immune cell homing compared to HIV-negative controls with similar glucose tolerance.
Highlights
People living with human immunodeficiency virus (HIV) are at an increased risk of developing insulin resistance and overt diabetes mellitus, but the factors contributing to the high prevalence of metabolic disease in the HIV population are not fully understood [1,2,3]
We show that expression of CD69, a putative marker of T cell receptor (TCR)-linked activation and tissue residency, increased on CD4+ TEM and TEMRA cells in a stepwise manner from non-diabetic, to pre-diabetic, to diabetic individuals
We demonstrate that the adipose tissue of people living with HIV (PLWH) is a reservoir of CD4+ and CD8+ TEM and TEMRA cells; two cell types with high pro-inflammatory potential when stimulated
Summary
People living with human immunodeficiency virus (HIV) are at an increased risk of developing insulin resistance and overt diabetes mellitus, but the factors contributing to the high prevalence of metabolic disease in the HIV population are not fully understood [1,2,3]. Several studies describe profound changes in adipose tissue T cell populations during chronic HIV and simian immunodeficiency virus (SIV; a non-human primate virus similar to HIV) infections, which may influence adipose tissue metabolic function. These include changes in T cell surface marker phenotypes, cytokine production, antigen receptor repertoire, and capacity for latent infection with HIV or SIV provirus [17,18,19,20,21,22]. Several studies found that HIV and SIV were accompanied by a substantial increase in the proportion of adipose CD8+ T cells relative to CD4+ T cells, which is strikingly similar to the enrichment in CD8+ T cells described in obesity [23,24,25]
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