Activation requirements for the induction of CD4+CD25+ T cell suppressor function.
The in vivo differentiation/survival of CD4(+)CD25(+) T suppressor cells is dependent on IL-2 and CD28-mediated costimulatory signals. To determine the cytokine and costimulatory requirements for CD25(+) T cells in vitro, we established a two-stage culture system where CD25(+) T cells were activated in a primary culture. In the subsequent culture, activated CD4(+)CD25(+) cells were then mixed with responders in order to assess their suppressor function. Pre-culture of CD25(+) T cells with anti-CD3 alone resulted in poor survival and minimal induction of suppressor activity. Pre-culture in the presence of anti-CD3 and IL-2 or IL-4, but not IL-6, IL-7, IL-9, IL-10 or IL-15, resulted in proliferation of the CD25(+) cells and induction of potent suppressor function. Inhibition of the interaction of CD28 or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with CD80/CD86 in the pre-culture of CD4(+)CD25(+) cells did not prevent the induction of suppressor function. Furthermore, the inhibition of costimulatory signals did not inhibit the ability of fresh CD25(+) T cells to inhibit CD8(+) responders under conditions where activation of the responders was independent of CD80/CD86. These studies support the view that activation of CD25(+) T cells requires IL-2/IL-4 for their survival/differentiation into effector cells, but is independent of CD28/CTLA-4-mediated costimulation.
Thornton
Angela M
AM
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda 20892-1892, USA. athornton@niaid.nih.gov
Piccirillo
Ciriaco A
CA
Shevach
Ethan M
EM
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D002455:Cell Division / Q000276:immunology; D017635:Clonal Anergy; D005260:Female; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007376:Interleukin-2; D015375:Receptors, Interleukin-2