Tfh Cell Metabolism and HIV-1 Infection

Abstract

Abstract HIV-1 predominantly infects and depletes CD4 T cell populations. Multiple subsets of CD4 T cells exist, one of which is the follicular helper T (Tfh) subset. This subset is primarily present in lymphoid tissues, such as tonsil tissue, where it is specialized in helping B cells form germinal centers (GCs) for generation of high-affinity class-switched antibodies. Tfh cells in HIV-1 patients are expanded and become a major active and latent HIV-1 reservoir. To explore whether Tfh cells have a unique metabolic program that is responsible for Tfh cell expansion and survival under HIV-1 infection, we used flow cytometric analysis to sort GC Tfh (CD3+CD4+PD-1highCXCR5high) versus non-Tfh (CD3+CD4+PD-1−CXCR5−) cells from tonsil mononuclear cells for RNA sequencing (RNAseq). We found that Tfh cells express significantly lower levels of glycolytic genes, but higher levels of gluconeogenic and fatty acid oxidation genes. Inhibition of glycolysis via a lack of glucose in culture medium aided in the differentiation of Tfh cells from naive CD4 T cells and promoted Tfh cell survival against HIV-1 infection. Furthermore, use of chemical inhibition of alternative metabolic pathways effected the response of T cell subsets to HIV-1 infection. Our studies into metabolism in Tfh cells suggest a relationship between their unique metabolic phenotype and HIV-1 infection, replication and latency.