Inhibition of TNF receptor signaling by anti-TNFα biologicals primes naïve CD4(+) T cells towards IL-10(+) T cells with a regulatory phenotype and function

Abstract

TNFα is a potent pro-inflammatory cytokine playing a pivotal role in several autoimmune diseases. Little is known about the mechanism of TNFα blocking agents on naïve T cell differentiation. Here, we report that neutralizing TNFα during priming of naïve CD4(+) T cells by dendritic cells favors development of IL-10(+) T helper cells. TNFα counteracts IL-10(+) T cell priming mainly via TNFRI receptor signaling. While initial T cell activation was not affected, neutralization of TNFα negatively affected sustained T cell differentiation in later stages of T cell priming. Whole genome gene expression analysis revealed an extended regulatory gene profile for anti-TNFα-treated T cells. Indeed, neutralizing TNFα during naïve T cell priming enhanced the suppressive function of anti-TNFα-treated T cells. Taken together, inhibition of TNFα-TNFR interaction shifts the balance of Th cell differentiation towards IL-10 expressing suppressive T cells, which may be one of the beneficial mechanisms in TNFα blocking therapies.

Keywords: Anti-TNFα therapy; IL-10; Regulatory T cells; T cell polarization; TNF receptor.