α1β1 Integrin+ and Regulatory Foxp3+ T Cells Constitute Two Functionally Distinct Human CD4+ T Cell Subsets Oppositely Modulated by TNFα Blockade

Abstract

The expression of the collagen receptor α1β1 integrin (VLA-1) on CD4+ T cells is largely restricted to CCR7−CD45RO+ cells that localize to inflamed tissues. Moreover, neutralizing α1 integrin, in vivo, has been shown to compromise cell-mediated immunity. Our current study shows that the expression of VLA-1 on human CD4+ T cells is restricted to conventional effectors. In contrast, Foxp3+ T regulatory cells (Tregs) do not express this receptor. Moreover, Foxp3 or VLA-1 expression remained a mutually exclusive event in CD4+ T cells even upon polyclonal anti-CD3-induced activation. Because TNFα blockade ameliorates certain T cell-dependent autoimmune disorders in humans, we investigated, in vitro, whether neutralizing TNFα affected the balance between the proinflammatory VLA-1+ effectors and the counteracting Tregs. We found that anti-CD3 stimulation of freshly isolated PBL from healthy individuals, coupled with continuous TNFα blockade, inhibited the typical activation-dependent generation of CD4+VLA-1+ Th1 cells. In contrast, it augmented the outgrowth of VLA-1neg/dimCD25high and Foxp3+CD4+ T cells. Indeed, repeated anti-CD3 stimulation coupled with TNFα blockade generated CD4+ T cell lines enriched for VLA-1−Foxp3+ Tregs. Importantly, these CD4+ T cells displayed potent suppressive functions toward autologous CD4+ PBL, including the suppression of the activation-dependent induction of VLA-1+ effectors. Thus, we propose a novel mechanism by which anti-TNFα therapy may restore self-tolerance, by shifting the balance between VLA-1+ effectors and Foxp3+ Tregs, during immune activation, in favor of the latter suppressor cell population.