Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy
Andrew D. Wells, … , Jeffrey A. Bluestone, Laurence A. Turka
Andrew D. Wells, … , Jeffrey A. Bluestone, Laurence A. Turka
Published September 15, 2001
Citation Information: J Clin Invest. 2001;108(6):895-904. https://doi.org/10.1172/JCI13220.
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Signaling through CD28 and CTLA-4 controls two distinct forms of T cell anergy

Abstract

Primary T cell proliferative responses to TCR ligation plus CD28 costimulation are surprisingly heterogeneous. Many cells that enter G1 fail to progress further through the cell cycle, and some of these cells subsequently fail to divide upon restimulation, even in the presence of IL-2. Such IL-2–refractory anergy is distinct from the IL-2–reversible anergy induced by TCR occupancy in the absence of CD28 costimulation. Here, we focus on the contributions of cell cycle progression and costimulatory (CD28/CTLA-4) signals in the regulation of anergy. We show that CD28 costimulation is not sufficient for anergy avoidance and that activated T cells must progress through the 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 cells that undergo multiple rounds of cell division during overt CD28 costimulatory blockade do not escape the ultimate induction of clonal anergy. Anergy avoidance by primary T cells is thus a multistep process: in order to participate in a productive immune response, an individual T cell activated through its antigen receptor must receive CD28 costimulation and progress through 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 proliferation-independent mechanism in which TCR ligation occurs in the absence of CD28.

Authors

Andrew D. Wells, Matthew C. Walsh, Jeffrey A. Bluestone, Laurence A. Turka

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Figure 3

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Regulation of primary T cell division by B7–CTLA-4 interactions. (a) Poo...
Regulation of primary T cell division by B7–CTLA-4 interactions. (a) Pooled BALB/c lymph node and spleen cells were labeled with CFSE, and T cells were subjected to co-crosslinking of TCR and CD28 by the addition of polystyrene beads coated with anti-CD3 (1 μg/ml), anti-CD28 (1 μg/ml), and control hamster IgG (1 μg/ml). (b) In separate cultures, T cells were subjected to co-crosslinking of TCR, CD28, and CTLA-4 by the addition of polystyrene beads coated with anti-CD3 (1 μg/ml), anti-CD28 (1 μg/ml), and anti–CTLA-4 (1 μg/ml). Proliferation of the CD4+ T cell subset was assessed by flow cytometry 3 days later. The frequency of precursor T cells that divided in response to stimulus (RF), and the number of daughter T cells generated by the average responding precursor T cell (CP), were calculated as described previously (2, 3). The data are representative of two separate experiments.