Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons

Abstract

Background: Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially proinflammatory T-cell populations in adipose tissue among persons on long-term antiretroviral therapy and assess whether adipose tissue CD8 T cells represent an expanded, oligoclonal population.

Methods: We recruited 10 HIV-infected, non-diabetic, overweight or obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression. We collected fasting blood and subcutaneous abdominal adipose tissue to measure the percentage of CD4 and CD8 T cells expressing activation, exhaustion, late differentiation/senescence, and memory surface markers. We performed T-cell receptor (TCR) sequencing on sorted CD8 cells. We compared the proportion of each T-cell subset and the TCR repertoire diversity, in blood versus adipose tissue.

Results: Adipose tissue had a higher percentage of CD3CD8 T cells compared with blood (61.0% vs. 51.7%, P < 0.01) and was enriched for both activated CD8HLA-DR T cells (5.5% vs. 0.9%, P < 0.01) and late-differentiated CD8CD57 T cells (37.4% vs. 22.7%, P < 0.01). Adipose tissue CD8 T cells displayed distinct TCRβ V and J gene usage, and the Shannon Entropy index, a measure of overall TCRβ repertoire diversity, was lower compared with blood (4.39 vs. 4.46; P = 0.05).

Conclusions: Adipose tissue is enriched for activated and late-differentiated CD8 T cells with distinct TCR usage. These cells may contribute to tissue inflammation and impaired adipocyte fitness in HIV-infected persons.

Conflict of interest statement

Disclosures: No authors report any conflicts of interest or relevant financial relationships

Figures

Figure 1

Greater clonality of the CD8+ T cell receptor β repertoire in adipose tissue compared to blood Colored bars represent the relative proportion of all productive CD8+ T cell receptor (TCR)β sequences from each subject’s paired adipose tissue and blood that comprised the 10 most prevalent clones (red bar), the 100 most prevalent clones (dark orange bar), etc. Proportional downsampling and bootstrapping were used to account for read count distribution differences between tissue compartments. The 10 most prevalent TCRβ clones comprised a larger percentage of total clones in adipose tissue compared to paired blood in all 5 subjects (25% vs. 16% of total repertoire, respectively; P=0.04), and the Shannon’s Entropy index, a measure of overall repertoire diversity, was lower in adipose tissue compared to blood (4.39 vs. 4.46, respectively; P=0.05).

Figure 2

Distinct CD8+ T cell receptor β V and J gene arrangement distributions in adipose tissue compared to blood Circos plots showing the combinations of V and J genes used in the rearranged T cell receptor (TCR)β expressed by CD8+ T cells in adipose tissue and matched blood samples. For each subject, the left-sided plot represents sorted adipose tissue CD8+ T cells and the right-sided plot represents sorted blood CD8+ T cells. The upper section of each plot depicts TCRβ (abbreviated TRB) J genes and the lower section depicts V genes. The arc length of each colored block denotes the relative frequency at which the gene family was identified. Rearrangement of a J gene with a V gene segment in a clonal TCR sequence is represented by a ribbon carrying the color of the J gene family to the color of the V gene family participating in the pairing. The width of the ribbon corresponds to the frequency at which each particular V-J rearrangement occurs in the TCR repertoire.