B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28 - PubMed (original) (raw)

B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28

F Fallarino et al. J Exp Med. 1998.

Abstract

Ligation of cytotoxic T lymphocyte antigen 4 (CTLA4) appears to inhibit T cell responses. Four mechanisms have been proposed to explain the inhibitory activity of CTLA4: competition for B7-1 and B7-2 binding by CD28; sequestration of signaling molecules away from CD28 via endocytosis; delivery of a signal that antagonizes a CD28 signal; and delivery of a signal that antagonizes a T cell receptor (TCR) signal. As three of these potential mechanisms involve functional antagonism of CD28, an experimental model was designed to determine whether CTLA4 could inhibit T cell function in the absence of CD28. TCR transgenic/recombinase activating gene 2-deficient/CD28-wild-type or CD28-deficient mice were generated and immunized with an antigen-expressing tumor. Primed T cells from both types of mice produced cytokines and proliferated in response to stimulator cells lacking B7 expression. However, whereas the response of CD28+/+ T cells was augmented by costimulation with B7-1, the response of the CD28-/- T cells was strongly inhibited. This inhibition was reversed by monoclonal antibody against B7-1 or CTLA4. Thus, CTLA4 can potently inhibit T cell activation in the absence of CD28, indicating that antagonism of a TCR-mediated signal is sufficient to explain the inhibitory effect of CTLA4.

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Figures

Figure 1

Figure 1

Flow cytometric analysis of T cells from mutant mice. 2C/Rag/CD28+/+ and CD28−/− mice were immunized by in vivo rejection of P1.HTR tumor cells. Splenic T cells were purified and restimulated for 2 d with mitomycin C–treated P815 cells to assess expression of TCR, CD28, and CTLA4. Flow cytometric analysis was performed after surface staining using the clonotypic TCR antibody 1B2 or the anti-CD28 mAb 37.51, or after intracellular staining with the anti-CTLA4 mAb 4F10. Similar results were obtained in three separate experiments.

Figure 2

Figure 2

Time course of proliferation of CD28+/+ or CD28−/− TCR Tg T cells in response to B7-1+ or B7-1− stimulator cells. CD8+ T cells purified by negative selection from primed CD28+/+or CD28−/− 2C/Rag2−/− mice were stimulated with mitomycin C–treated P815 or P815.B71 cells. Replicate cultures were pulsed daily with [3H]thymidine and harvested, and incorporated radioactivity was assessed. Similar results were obtained in at least two experiments.

Figure 3

Figure 3

Cytokine production by CD28+/+ or CD28−/− TCR Tg T cells in response to B7-1+ or B7-1− stimulator cells. CD8+ T cells purified as in Fig. 2 were stimulated with mitomycin C–treated P815 or P815.B71 cells. Supernatants were collected, and IL-2 and IFN-γ content were assessed. Similar results were obtained in at least three experiments.

Figure 4

Figure 4

Inhibition of cytokine production of CD28−/− T cells by B7-1 transfectants is prevented by anti–B7-1 or by anti-CTLA4 mAb. T cell stimulations were performed as in Fig. 3 without additions, or in the presence of anti–B7-1 mAb, anti-CTLA4 mAb, or the combination. IL-2 production was determined at 24 h. Similar results were obtained for IFN-γ production (data not shown), and in at least two separate experiments.

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