Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy

Primary T cell proliferative responses to TCR ligation plus CD28 costimulat ion are surprisingly heterogeneous. Many cells that enter G1 fail to progre ss further through the cell cycle, and some of these cells subsequently fai l to divide upon restimulation, even in the presence of IL-2. Such IL-2-ref ractory anergy is distinct from the IL-2-reversible anergy induced by TCR o ccupancy in the absence of CD28 costimulation. Here, we focus on the contri butions of cell cycle progression and costimulatory (CD28/CTLA-4) signals i n the regulation of anergy. We show that CD28 costimulation is not sufficie nt for anergy avoidance and that activated T cells must progress through th e cell cycle in order to escape anergy. Induction of this "division-arrest" form of anergy requires CTLA-4 signaling during the primary response. Also , cell division per se is not sufficient for anergy avoidance: the few T ce lls that undergo multiple rounds of cell division during overt CD28 costimu latory blockade do not escape the ultimate induction of clonal anergy. Aner gy avoidance by primary T cells is thus a multistep process: in order to pa rticipate in a productive immune response, an individual T cell activated t hrough its antigen receptor must receive CD28 costimulation and progress th rough the cell cycle. Anergy may be induced either through a combination of CTLA-4 signaling and the failure of cell cycle progression, or through a p roliferation-independent mechanism in which TCR ligation occurs in the abse nce of CD28.