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-x(L) 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-gamma 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.
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机译：自相矛盾地给予激动性抗 CD28 mAb 可抑制供体 T 细胞扩增并预防小鼠移植物抗宿主病 （GVHD）。在这里，我们研究了抗CD28介导的免疫抑制机制，发现抗CD28单克隆抗体在体内激活而不是阻断CD28介导的信号传导。抗 CD28 治疗通过细胞凋亡选择性地消耗同种抗原激活的供体 T 细胞来预防 GVHD，但保留了不识别受体同种异体抗原的 T 细胞。Bcl-x（L） 的过表达不能保护 T 细胞免于耗竭，并且不影响抗 CD28 治疗后的 GVHD 预防。通过 CD28 介导的活化 T 细胞的耗竭不取决于死亡受体 Fas 和 TNF 受体 I 型和 II 型的表达，但活化 T 细胞的耗竭和抗 CD28 单克隆抗体对 GVHD 致死性的抑制作用都需要供体来源的 IFN-γ 的产生。这项研究表明，对 CD28 共刺激分子具有特异性的激动性抗体可用作新型治疗剂，通过选择性耗竭活化的 T 细胞来消除致病性 T 细胞反应。
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