A critical precursor frequency of donor-reactive CD4+ T cell help is required for CD8+ T cell-mediated CD28/CD154-independent rejection.
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.
Ford
Mandy L
ML
Department of Surgery and Emory Transplant Center, Emory University, Atlanta, GA 30322, USA. mandy.ford@emory.edu
Wagener
Maylene E
ME
Hanna
Samantha S
SS
Pearson
Thomas C
TC
Kirk
Allan D
AD
Larsen
Christian P
CP
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D018106:CD28 Antigens; D016207:Cytokines; D023201:CD40 Ligand