Clonal anergy is maintained independently of T cell proliferation.
Ag encounter in the absence of proliferation results in the establishment of T cell unresponsiveness, also known as T cell clonal anergy. Anergic T cells fail to proliferate upon restimulation because of the inability to produce IL-2 and to properly regulate the G(1) cell cycle checkpoint. Because optimal TCR and CD28 engagement can elicit IL-2-independent cell cycle progression, we investigated whether CD3/CD28-mediated activation of anergic T cells could overcome G(1) cell cycle block, drive T cell proliferation, and thus reverse clonal anergy. We show here that although antigenic stimulation fails to elicit G(1)-to-S transition, anti-CD3/CD28 mAbs allow proper cell cycle progression and proliferation of anergic T cells. However, CD3/CD28-mediated cell division does not restore Ag responsiveness. Our data instead indicate that reversal of clonal anergy specifically requires an IL-2-dependent, rapamycin-sensitive signal, which is delivered independently of cell proliferation. Thus, by tracing proliferation and Ag responsiveness of individual cells, we show that whereas both TCR/CD28 and IL-2-generated signals can drive T cell proliferation, only IL-2/IL-2R interaction regulates Ag responsiveness, indicating that proliferation and clonal anergy can be independently regulated.
Colombetti
Sara
S
Cancer Immunotherapy and Gene Therapy Program, DIBIT/S. Raffaele Scientific Institute, Milan, Italy.
Benigni
Fabio
F
Basso
Veronica
V
Mondino
Anna
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000941:Antigens / Q000008:administration & dosage; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002455:Cell Division; D017635:Clonal Anergy; D002999:Clone Cells; D016193:G1 Phase; D007376:Interleukin-2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000941:Antigens; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D011994:Recombinant Proteins; D010047:Ovalbumin; D020123:Sirolimus