A critical precursor frequency of donor-reactive CD4+ T cell help is required for CD8+ T cell-mediated CD28/CD154-independent rejection

Mandy L. Ford, Maylene E. Wagener, Samantha S. Hanna, Thomas C. Pearson, Allan D. Kirk, Christian P. Larsen

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Ag-specific precursor frequency is increasingly being appreciated as an important factor in determining the kinetics, magnitude, and degree of differentiation of T cell responses, and recently was found to play a critical role in determining the relative requirement of CD8+ T cells for CD28- and CD154-mediated costimulatory signals during transplantation. We addressed the possibility that variations in CD4+ T cell precursor frequency following transplantation might affect CD4+ T cell proliferation, effector function, and provision of help for donor-reactive B cell and CD8+ T cell responses. Using a transgenic model system wherein increasing frequencies of donor-reactive CD4+ T cells were transferred into skin graft recipients, we observed that a critical CD4 + T cell threshold precursor frequency was necessary to provide help following blockade of the CD28 and CD154 costimulatory pathways, as measured by increased B cell and CD8+ T cell responses and precipitation of graft rejection. In contrast to high-frequency CD8+ T cell responses, this effect was observed even though the proliferative and cytokine responses of Ag-specific CD4+ T cells were inhibited. Thus, we conclude that an initial high frequency of donor-reactive CD4+ T cells uncouples T cell proliferative and effector cytokine production from the provision of T cell help.

Original languageEnglish
Pages (from-to)7203-7211
Number of pages9
JournalJournal of Immunology
Volume180
Issue number11
DOIs
StatePublished - 2008
Externally publishedYes

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