The CD154-CD40 T cell costimulation pathway is required for host sensitization of CD8+ T cells by skin grafts via direct antigen presentation

Yuan Zhai, Xiu Da Shen, Feng Gao, Ana J. Coito, Barbara A. Wasowska, Alan Salama, Isabela Schmitt, Ronald W. Busuttil, Mohamed H. Sayegh, Jerzy W. Kupiec-Weglinski

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Abstract

Although the CD154-CD40 T cell costimulation pathway has been shown to mediate alloimmune responses in normal recipients, little is known about its role in sensitized hosts. In this work, by using novel models of cardiac allograft rejection in skin-sensitized CD154- and CD40-deficient mice, we reaffirm the key role of CD154-CD40 signaling in host sensitization to alloantigen in vivo. First, we identified CD8+ T cells as principal effectors in executing accelerated rejection in our model. Disruption of CD154-CD40 signaling in recipients at the T cell side (CD154-deficient) but not at the APC side (CD40-deficient) abrogated accelerated (100 days) graft survival. This suggests that the CD154-dependent mechanism in host CD8+ T cell sensitization operates via the direct Ag presentation. Then, in comparative studies of alloimmune responses in CD154-deficient and wild-type recipients, we showed that, although alloreactive B cell responses were inhibited, alloreactive T cell responses were down-regulated selectively in the CD8+ T cell compartment, leaving CD4+ T cells largely unaffected. This unique alteration in host alloreactivity, seen not only in peripheral lymphocytes but also in allograft infiltrate, may represent the key mechanism by which disruption of CD154-CD40 signaling prevents sensitization to alloantigen in vivo and leads to long-term allograft survival.

Original languageEnglish (US)
Pages (from-to)1270-1276
Number of pages7
JournalJournal of Immunology
Volume169
Issue number3
StatePublished - Aug 1 2002
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

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Zhai, Y., Shen, X. D., Gao, F., Coito, A. J., Wasowska, B. A., Salama, A., Schmitt, I., Busuttil, R. W., Sayegh, M. H., & Kupiec-Weglinski, J. W. (2002). The CD154-CD40 T cell costimulation pathway is required for host sensitization of CD8+ T cells by skin grafts via direct antigen presentation. Journal of Immunology, 169(3), 1270-1276.