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A Critical Precursor Frequency of Donor-Reactive CD4⁺ T Cell Help Is Required for CD8⁺ T Cell-Mediated CD28/CD154-Independent Rejection¹

Department of Surgery and Emory Transplant Center, Emory University, Atlanta, GA 30322

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI (to C.P.L.). M.L.F. was supported by a Ruth L. Kirschstein National Research Service Award.

² Address correspondence and reprint requests to Dr. Mandy L. Ford, Emory University, 101 Woodruff Circle, Woodruff Memorial Building Suite 5105, Atlanta, GA 30322. E-mail address: mandy.ford{at}emory.edu

³ Abbreviations used in this paper: mOVA, membrane-bound chicken OVA; LN, lymph node; DLN, draining LN; MST, median survival time; DC, dendritic cell.

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The JI 2008 180: 7053-7054. [Full Text]  

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