α₁β₁ integrin⁺ and regulatory Foxp3⁺ T cells constitute two functionally distinct human CD4 ⁺ T cell subsets oppositely modulated by TNFα blockade

The expression of the collagen receptor α₁β ₁ integrin (VLA-1) on CB4⁺ 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-1^neg/dimCD25^high 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.