Inhibition of TNF receptor signaling by anti-TNF伪 biologicals primes na茂ve CD4⁺ T cells towards IL-10⁺ T cells with a regulatory phenotype and function

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• 作者：Martine A. Boks ; Judith R. Kager-Groenland ; Charlotte M. Mousset ; S. Marieke van Ham ; Anja ten Brinke ; ^{a.tenbrinke@sanquin.nl" class="auth_mail}
• 关键词：mTNF伪 ; transmembrane TNF伪 ; RA ; rheumatoid arthritis ; sTNF伪 ; soluble TNF伪 ; tDC ; tolerogenic dendritic cell ; TNFR ; TNF伪 receptor
• 刊名：Clinical Immunology
• 出版年：April, 2014
• 年：2014
• 卷：151
• 期：2
• 页码：136-145
• 全文大小：651 K

文摘

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