Foxp3+ regulatory T cells are activated in spite of B7-CD28 and CD40-CD40L blockade.
Costimulatory signals are required for priming and activation of naive T cells, while it is less clear how they contribute to induction of regulatory T (Treg)-cell activity. We previously reported that the blockade of the B7-CD28 and CD40L-CD40 interaction efficiently suppresses allogeneic T-cell activation in vivo. This was characterized by an initial rise in Foxp3(+) cells, followed by depletion of host-reactive T cells. To further investigate effects of costimulatory blockade on Treg cells, we used an in vitro model of allogeneic CD4(+) cell activation. When CTLA-4Ig and anti-CD40L mAb (MR1) were added to the cultures, T-cell proliferation and IL-2 production were strongly reduced. However, Foxp3(+) cells proliferated and acquired suppressive activity. They suppressed activation of syngeneic CD4(+) cells much more efficiently than did freshly isolated Treg cells. CD4(+) cells activated by allogeneic cells in the presence of MR1 and CTLA-4Ig were hyporesponsive on restimulation, but their response was restored to that of naive CD4(+) cells when Foxp3(+) Treg cells were removed. We conclude that natural Treg cells are less dependent on B7-CD28 or CD40-CD40L costimulation compared with Foxp3(-) T cells. Reduced costimulation therefore alters the balance between Teff and Treg-cell activation in favor of Treg-cell activity.
Laboratory of Clinical Immunology, Faculty of Medicine, KU Leuven, Leuven, Belgium.
Isabel
I
Vogel
Bert
B
Verbinnen
Wim
W
Maes
Louis
L
Boon
Stefaan W
SW
Van Gool
Jan L
JL
Ceuppens
D000069594:Abatacept; D000818:Animals; D060887:B7 Antigens / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000494:pharmacology; D018796:Immunoconjugates / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D015778:Minor Histocompatibility Antigens; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
D060887:B7 Antigens; D018106:CD28 Antigens; D019013:CD40 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015395:Histocompatibility Antigens Class I; D018796:Immunoconjugates; D015778:Minor Histocompatibility Antigens; C490628:Mr1 protein, mouse; D023201:CD40 Ligand; D000069594:Abatacept