Original Article

CD40 Ligand (CD154) Triggers a Short-Term CD4⁺ T Cell Activation Response That Results in Secretion of Immunomodulatory Cytokines and Apoptosis

Correspondence to: Patrick J. Blair, NIDDK-Navy Transplantation and Autoimmunity Branch (034), Naval Medical Research Center, 8901 Wisconsin Ave., Bethesda, MD 20889-5607. Tel:301-295-2388 Fax:301-295-6484 E-mail:blairp{at}nmripo.nmri.nnmc.navy.mil.

Signals generated through CD28–B7 and CD40 ligand (CD40L)–CD40 interactions have been shown to be crucial for the induction of long-term allograft survivability. We have recently demonstrated that humanized anti-CD40L (hu5C8) prevents rejection of mismatched renal allografts in primates. To investigate potential mechanisms of CD40L–induced allograft acceptance, we coimmobilized hu5C8 with suboptimal amounts of anti-CD3 to stimulate CD4⁺ T cells. We now report that anti-CD3/CD40L costimulation results in CD28-independent activation and subsequent deletion of resting T cells. Coligation of CD3 and CD40L increased expression of CD69, CD25, and CD54 on CD4⁺ T cells. We also found that costimulation with anti-CD3/CD40L resulted in enhanced production of interleukin (IL)-10, interferon , and tumor necrosis factor but not IL-2 or IL-6. Interestingly, after several days, anti-CD3/CD40L–mediated activation was followed by apoptosis in a significant population of cells. Consistent with that observation, anti-CD3/CD40L did not enhance the antiapoptotic proteins Bcl-2 and Bcl-xL. Further, the addition of CD28 at 24 h failed to rescue those cells induced to die after costimulation with anti-CD3/CD40L. Together, these data suggest that the graft-sparing effect of hu5C8 in vivo may result in part from early and direct effects on CD4⁺ T cells, including a vigorous induction of immunomodulatory cytokines and/or apoptosis of allograft-specific T cells.

Key Words: costimulatory molecules, T lymphocytes, transplantation, cytokines, apoptosis

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