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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Article

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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Regulation of T cell IL-2 production by both B7-mediated costimulation a...
Regulation of T cell IL-2 production by both B7-mediated costimulation and cell division. (a) Pooled BALB/c lymph node and spleen cells were labeled with CFSE, and T cells were stimulated in the presence of endogenous B7-mediated costimulation by the addition of soluble anti-CD3 antibody (1 μg/ml). (b) Alternatively, B7-mediated costimulation was blocked during primary activation by the addition of CTLA4Ig (15 μg/ml). After 4 days, cultures were washed, plated in fresh medium, and rested for an additional 48 hours. T cells were then restimulated for 5 hours by the addition of polystyrene beads (5 μm) coated with anti-CD3 (5 μg/ml) and anti-CD28 (5 μg/ml) antibodies, and the frequency of CD4+ cells producing IL-2 was assessed by flow cytometry. Plots show IL-2 production as a function of cell division (CFSE fluorescence) in the CD4+ T cell subset. Vertical lines delineate the divided from the undivided cells, and horizontal lines denote the maximal fluorescence of cells stained with isotype control antibody. Values in each corner represent the proportion of the CD4+ events that fall in each quadrant. Cells cultured in medium with no stimulus and stained with specific antibody were less than 0.1% positive for IL-2. These data are representative of three independent experiments. The frequency of IL-2 producers among CD3/CD28-primed T cells varied from experiment to experiment (range: ∼10–35%); however, the frequency of IL-2 producers in cultures primed in the presence of CTLA4Ig was consistently reduced two- to fourfold.