The Journal of Experimental Medicine
VeriKine-HS Human Interferon-Beta Serum
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© The Rockefeller University Press, 0022-1007/2000/2/651/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 4, February 21, 2000 651-660

Original Article

Cd40 Ligand (Cd154) Triggers a Short-Term Cd4+ T Cell Activation Response That Results in Secretion of Immunomodulatory Cytokines and Apoptosis

Patrick J. Blaira, James L. Rileyb, David M. Harlana, Ryo Abec, Douglas K. Tadakia, Steven C. Hoffmanna, Leonard Whitea, Tara Francomanoa,d, Stephen J. Perfettod, Allan D. Kirka, and Carl H. Juneb

a From the National Institute of Diabetes and Digestive and Kidney Diseases–Navy Transplantation and Autoimmunity Branch, Naval Medical Research Center, Bethesda, Maryland 20889-5607
b University of Pennsylvania, Philadelphia, Pennsylvania 19104
c Research Institute for Biological Sciences, Science University of Tokyo, Chiba 278-0022, Japan
d Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland 20889
NIDDK-Navy Transplantation and Autoimmunity Branch (034), Naval Medical Research Center, 8901 Wisconsin Ave., Bethesda, MD 20889-5607.301-295-6484301-295-2388

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 {gamma}, and tumor necrosis factor {alpha} 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

Abbreviations used in this paper: CSA, cyclosporin A; CTLA4-Ig, CTL-associated antigen 4–Ig; hu5C8, humanized anti-CD40L mAb clone 5C8; RT, reverse transcriptase; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling.

© 2000 The Rockefeller University Press


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