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

TNF alpha is a potent pro-inflammatory cytokine playing a pivotal role in several autoinnmune diseases. Little is known about the mechanism of TNF alpha blocking agents on naive T cell differentiation. Here, we report that neutralizing TNF alpha during priming of na ve CD4(+) T cells by dendritic cells favors development of IL-10(+) T helper cells. TNF alpha counteracts IL-10(+) T cell priming mainly via TNFRI receptor signaling. While initial T cell activation was not affected, neutralization of TNF alpha 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-TNF alpha-treated T cells. Indeed, neutralizing TNFa during na ve T cell priming enhanced the suppressive function of anti-TNF alpha-treated T cells. Taken together, inhibition of TNF alpha-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 TNF alpha blocking therapies.(c) 2014 Elsevier Inc. All rights reserved.