CD28 ligation induces transplantation tolerance by IFN-γ–dependent depletion of T cells that recognize alloantigens
Xue-Zhong Yu, … , Paul J. Martin, Claudio Anasetti
Xue-Zhong Yu, … , Paul J. Martin, Claudio Anasetti
Published June 1, 2004
Citation Information: J Clin Invest. 2004;113(11):1624-1630. https://doi.org/10.1172/JCI20940.
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CD28 ligation induces transplantation tolerance by IFN-γ–dependent depletion of T cells that recognize alloantigens

Abstract

Administration of an agonistic anti-CD28 mAb paradoxically inhibits donor T cell expansion and prevents graft-versus-host disease (GVHD) in mice. Here we examined the mechanism of anti-CD28–mediated immunosuppression and found that anti-CD28 mAb activated, rather than blocked, CD28-mediated signaling in vivo. Anti-CD28 treatment prevented GVHD by selectively depleting alloantigen-activated donor T cells through apoptosis but spared the T cells that did not recognize recipient alloantigens. Overexpression of Bcl-xL did not protect T cells from depletion and did not affect GVHD prevention after anti-CD28 treatment. Depletion of activated T cells mediated through CD28 did not depend on the expression of death receptors Fas and TNF receptors type I and II, but both the depletion of activated T cells and the suppressive effect of anti-CD28 mAb on GVHD lethality required donor-derived IFN-γ production. This study demonstrates that agonistic Ab’s specific for the CD28 costimulatory molecule may be used as novel therapeutic agents to abrogate pathogenic T cell responses by selective depletion of activated T cells.

Authors

Xue-Zhong Yu, Michael H. Albert, Paul J. Martin, Claudio Anasetti

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Anti-CD28 mAb provides costimulatory signals to T cells in vivo. (A) Ant...
Anti-CD28 mAb provides costimulatory signals to T cells in vivo. (A) Anti-CD28 mAb increases cytokine mRNA levels in activated T cells in vivo. DO11.10 WT (lanes 1–4) or CD28-deficient (lanes 5 and 6) mice were injected with control mAb plus control peptide (lanes 1 and 5), anti-CD28 mAb plus control peptide (lane 2), control mAb plus OVA peptide (lanes 3 and 6), or anti-CD28 mAb plus OVA peptide (lane 4). One hour after injection, spleens were harvested, and RPA was used to measure cytokine mRNA levels. The lower portion of the gel was exposed to the x-ray film for a much shorter period of time than was the upper portion in order to produce bands of similar intensity for L32 and GAPDH as for other probes. Each band represents one of two mice in the group. Results from one of three representative experiments are shown. (B) Anti-CD28 mAb increases IL-2 expression among activated T cells in vivo. B6 CD80/CD86–deficient mice were injected intravenously with 100 ∝g of anti-CD28 mAb, 10 ∝g/mouse of SEA, or both in combination. Splenocytes were stained for surface expression of CD4 and TCR Vβ3,11 and for intracellular expression of IL-2. The data shown are intracellular IL-2 expression on gated CD4+/TCR Vβ3,11+ (SEA-reactive) cells. (C) Anti-CD28 mAb increases IL-2 production in the serum. Data are shown as averages of two mice in each group with error bars indicating 1 SD. Results represent one of two replicate experiments.