Th140 - The Role of Activin a in T-cell Mediated Modulation of Monocyte Function

Abstract Text: Monocytes are key drivers of inflammation; therefore, understanding how these cells can be modulated is scientifically and clinically relevant.
Healthy control peripheral blood-derived CD14+ monocytes were cultured with activated autologous CD4+CD25- effector T-cells (Teffs) or CD4+CD25+CD127- regulatory T-cells (Tregs). RNA-seq analysis revealed that Teffs and Tregs differentially altered the transcriptional signature of monocytes (n=11). The top upregulated gene in Teff-modulated monocytes was INHBA (Log2FC 7.5), encoding activin A, a pleiotropic cytokine present during inflammation. Furthermore, Teff-modulated CD14+ monocytes displayed reduced mRNA and protein expression of the scavenger receptor CD36 (n=11) and showed reduced uptake of ox-LDL (n=6). Stimulation of monocytes with recombinant TNFα similarly reduced the expression of CD36 and uptake of ox-LDL, with an additive effect of Activin A. This further substantiates the modulatory effect of Activin A in the interaction between monocytes and Teff.
Data mining of a pre-existing transcriptomic dataset of blood and joint-derived T-cells from patients with rheumatoid arthritis showed the activin A receptors ALK4 and ACVR2A/B are present on Teffs. Flow analysis of CD4+ T-cells stimulated with activin A showed an increased frequency of TNFα-expressing T-cells (n=5). The increase in TNFα-expressing cells was observed across different CD4+ T-cell subsets (IFN-γ+, IL-10+, IL-17A+ and GM-CSF+) suggesting activin A alters the polyfunctional profile of CD4+ T-cells.
Together, these findings indicate a positive feedback loop, involving TNFα and activin A, between Teffs and monocytes resulting in impaired ox-LDL uptake.
Supported by King’s College London BHF Centre of Research Excellence [RE/24/130035] studentship to KJL and BBSRC studentship to AKD.