alpha1beta1 Integrin+ and regulatory Foxp3+ T cells constitute two functionally distinct human CD4+ T cell subsets oppositely modulated by TNFalpha blockade.
The expression of the collagen receptor alpha(1)beta(1) integrin (VLA-1) on CD4(+) T cells is largely restricted to CCR7(-)CD45RO(+) cells that localize to inflamed tissues. Moreover, neutralizing alpha(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 TNFalpha blockade ameliorates certain T cell-dependent autoimmune disorders in humans, we investigated, in vitro, whether neutralizing TNFalpha 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 TNFalpha blockade, inhibited the typical activation-dependent generation of CD4(+)VLA-1(+) Th1 cells. In contrast, it augmented the outgrowth of VLA-1(neg/dim)CD25(high) and Foxp3(+)CD4(+) T cells. Indeed, repeated anti-CD3 stimulation coupled with TNFalpha 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-TNFalpha 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.
Goldstein
Itamar
I
Laboratory for Immunoregulation, Chaim Sheba Medical Center, Tel Aviv University, Tel Hashomer, Israel. Itamar.Goldstein@sheba.health.gov.il
Ben-Horin
Shomron
S
Koltakov
Alexander
A
Chermoshnuk
Helly
H
Polevoy
Victor
V
Berkun
Yakov
Y
Amariglio
Ninette
N
Bank
Ilan
I
D000906:Antibodies / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D039222:Integrin alpha1beta1 / Q000819:agonists / Q000032:analysis*; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000819:agonists; D017634:Self Tolerance; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000906:Antibodies; D017252:CD3 Complex; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D039222:Integrin alpha1beta1; D053645:Interleukin-2 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha