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Global gene expression analysis of CD14+ monocytes and CD4+ effector memory T cells before and during fingolimod treatment

ABSTRACT: Treatment of multiple sclerosis (MS) patients with sphingosine-1-phosphate receptor agonist fingolimod (FTY) increases for unknown reasons the risk for symptomatic reactivation of alpha-herpesviruses, in particular of varicella zoster virus (VZV), but not of other co-infecting herpesviruses (e.g. human cytomegalovirus (HCMV). To elucidate this specific signal in adverse events, we systematically assessed changes in global and herpesvirus-specific immune responses and signatures in MS patients before and during FTY therapy. In addition to phenotypical and functional changes, we thought to identify FTY-induced modifications on the gene expression level, which might add to perturbations in antiviral immune responses. Therefore, gene expression of CD4+ EM T cells and CD14+ monocytes were analyzed. These two subsets, CD4+ EM T cells and CD14+ monocytes, were isolated from PBMC of six female RRMS patients collected before (V0) and after 9 months of FTY therapy (V9) for RNA sequencing (RNASeq). Comparison of gene expression profiles of monocytes between V0 and V9 revealed 226 down- and 38 upregulated genes. Gene ontology categories and pathway analysis detected most significant alterations for genes involved in immune response, defense against viruses as well as type-1 interferon signaling pathways. Next, we compared gene expression profiles of CD4+ EM T cells collected at V0 and V9 of FTY therapy and found 314 down- and 219 upregulated genes. The most significantly modified pathways were involved in immune responses, including NK cell chemotaxis, cytotoxicity and antiviral responses. In summary, gene expression analysis of monocytes suggests that HCMV might be more susceptible to reactivation during FTY treatment because of FTY-induced modifications of immune control pathways important for HCMV latency. However, increased cytolytic potential of CD4+ EM T cells and expansion of HCMV-specific CD4+ T cells might counteract synthesis or release of viral particles and prevent viremia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120375 | GEO | 2023/12/21

REPOSITORIES: GEO

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Project description:Persistent and elevated systemic inflammation contributes to the increased risk of cardiovascular and metabolic diseases in persons with HIV (PWH). , but aspects of the innate and adaptive immune response to HIV and other chronic co-infections that promote the development of these comorbid conditions remain unclear. We used mass cytometry and the tracking responders expanding (T-REX) workflow to define differences in circulating cells of the innate and adaptive immune arms, which differentiate non-diabetic and prediabetic/diabetic persons with HIV (PWH) on long-term antiretroviral therapy (ART). We found a significantly higher proportion of circulating CD14+ monocytes complexed with T cells, B cells, and NK cells among PWH with diabetes. The CD3+ T cells in these complexes were predominantly CD8+ memory T cells. The CD3+ CD14+ T cell-monocyte complexes are pro-inflammatory and negatively associated with plasma interleukin-10 levels and circulating CD4+ T regulatory cells. Using transmission electron microscopy, we observed heterogeneous interactions between CD3+ T cells and monocytes within the complexes, including formation of immune synapses and phagocytosis. 10x Chromium single-cell sequencing RNA transcriptomic analysis of CD3+ CD14+ doublets showed differential expression of genes involved in T cell activation and the adaptive immune response compared to monocytes that were not complexed with other immune cells. Notably, there were significantly more copies of HIV RNA per cell in the CD3+ CD14+ T cell-monocyte complexes compared to CD14+ monocytes or CD3+ CD4+ T cells alone, and HIV virions were observed in both T cells and monocytes within the doublets?. Metabolically, CD3+ CD14+ T cell-monocyte complexes had high glucose-dependence with minimal mitochondrial dependence. Taken together, CD3+ CD14+ T cell-monocyte pairs are functional and physically interacting immune cell complexes which might be enriched with HIV. These complexesare increased among individuals with diabetes and may be a target for future HIV cure studies and diseases of aging.

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Global gene expression analysis of CD14+ monocytes and CD4+ effector memory T cells before and during fingolimod treatment

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