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₁₁ Integrin⁺ and Regulatory Foxp3⁺ T Cells Constitute Two Functionally Distinct Human CD4⁺ T Cell Subsets Oppositely Modulated by TNF Blockade¹

Itamar Goldstein^2,, Shomron Ben-Horin, Alexander Koltakov^*, Helly Chermoshnuk, Victor Polevoy^*, Yakov Berkun, Ninette Amariglio and Ilan Bank^2,*,

^* Laboratory for Immunoregulation, Sheba Cancer Research Center, and Department of Medicine and Department of Pediatrics, Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel

The expression of the collagen receptor ₁₁ integrin (VLA-1) on CD4⁺ T cells is largely restricted to CCR7^–CD45RO⁺ cells that localize to inflamed tissues. Moreover, neutralizing ₁ 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 TNF blockade ameliorates certain T cell-dependent autoimmune disorders in humans, we investigated, in vitro, whether neutralizing TNF 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 TNF 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 TNF 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-TNF 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded in part by an investigator initiated nonrestricted grant from Biogen-Idec (to I.B.).

² Address correspondence and reprint requests to Dr. Itamar Goldstein, Sheba Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail address: Itamar.Goldstein{at}sheba.health.gov.il or Dr. Ilan Bank, Deptartment of Medicine, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail address: ibank{at}post.tau.ac.il

³ Abbreviations used in this paper: Treg, T regulatory cell; Foxp3, forkhead box P3; SFL, synovial fluid lymphocyte; RA, rheumatoid arthritis; JIA, juvenile idiopathic arthritis; rh, recombinant human; hIg, human Ig; Resp, responder; Supp, suppressor; Inflix-TC, infliximab-treated culture; con-TC, control-treated culture; LN, lymph node.

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