Tuomela, K. | Search bioRxiv

bioRxiv2024

TYK2 inhibition enhances Treg differentiation and function while preventing Th1 and Th17 differnetiation

Janus kinase (JAK) inhibitors are widely use to inhibit inflammatory cytokine signalling in autoimmune and inflammatory diseases but their effect on regulatory T cells (Tregs) is poorly characterized. We investigated the effect of JAK inhibition on human Treg differentiation, phenotype, and function using a JAK inhibitor, upadacitinib, in comparison to BMS-986202, a selective Tyrosine kinase 2 (TYK2) inhibitor. Both upadacitinib and BMS-986202 blocked the differentiation of naive CD4+ T cells into Th1 and Th17 cells, but only BMS-986202 spared IL-2 signalling and Treg differentiation. BMS-986202 also increased Treg suppressive function and stability under Th1- and Th17-polarizing conditions, whereas upadacitinib significantly impaired the phenotype and viability of ex vivo Tregs. Analysis of lamina propria mononuclear cells from patients with inflammatory bowel disease revealed that, under Th17 polarizing conditions, BMS-986202 redirected CD4+ T cells towards a Treg phenotype. The Treg-sparing and enhancing properties of TYK2 inhibition suggest that TYK2 inhibitors are a promising pharmacological approach for tolerance induction. eTOC SUMMARYTuomela et al. report that TYK2 inhibition does not affect human Treg induction from naive CD4+ T cells, promotes Treg differentiation in lamina propria-derived T cells, and increases blood-derived Treg stability/function. In contrast, JAK inhibition strongly impairs Treg function.

immunology↗

bioRxiv2024

Fourth generation CAR Tregs with PDCD1-driven IL-10 have enhanced suppressive function

The potency of regulatory T cell (Treg) therapy has been transformed through use of chimeric antigen receptors (CAR). However, to date, CAR Treg therapy has not achieved long-lasting tolerance in mouse models, suggesting that additional engineering is required to unlock the full potential of these cells. We previously found that human Tregs produce minimal amounts of IL-10 and have a limited capacity to control innate immunity in comparison to type I regulatory (Tr1) cells. Seeking to create "hybrid" CAR Tregs that were engineered with Tr1-like properties, we examined whether the PDCD1 locus could be exploited to endow Tregs with the ability to secrete high levels of IL-10 in a CAR-regulated manner. CRISPR-mediated PD1-deletion increased the activation potential of CAR Tregs without compromising in vivo stability. Knock-in of IL10 under control of the PD1 promoter facilitated CAR-mediated secretion of IL-10 in large quantities, and improved CAR Treg function, as determined by significant inhibition of dendritic cell antigen presentation and enhanced suppression of alloantigen- and islet autoantigen-specific T cells. Overall, CRISPR-mediated engineering to simultaneously remove an inhibitory signal and enhance suppressive mechanisms is a new approach to enhance the therapeutic potency of CAR Tregs.

immunology↗