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* Department of Surgery, Comprehensive Transplant Center, Ohio State University Medical Center, Columbus, OH 43210; and
Integrated Biomedical Science Graduate Program, College of Medicine, Ohio State University, Columbus, OH 43210
The role of CD4+ T cells in promoting CD8+ T cell effector activity in response to transplant Ags in vivo has not been reported. We used a hepatocellular allograft model known to initiate both CD4-dependent and CD4-independent rejection responses to investigate the contribution of CD4+ T cells to the development, function, and persistence of allospecific CD8+ T cell effectors in vivo. Complete MHC-mismatched hepatocellular allografts were transplanted into C57BL/6 (CD4-sufficient) or CD4 knockout (CD4-deficient) hosts. The development of in vivo allospecific cytotoxicity was determined by clearance of CFSE-labeled target cells. CD8+ T cell cytotoxic effector activity was enhanced in response to allogeneic hepatocellular grafts with a greater magnitude of allocytotoxicity and a prolonged persistence of CTL effector activity in CD4-sufficient hosts compared with CD4-deficient hosts. Cytolytic activity was mediated by CD8+ T cells in both recipient groups. In response to a second hepatocyte transplant, rejection kinetics were enhanced in both CD4-sufficient and CD4-deficient hepatocyte recipients. However, only CD4-sufficient hosts developed recall CTL responses with an augmented magnitude and persistence of allocytotoxicity in comparison with primary CTL responses. These studies show important functional differences between alloreactive CD8+ T cell cytolytic effectors that mature in vivo in the presence or absence of CD4+ T cells.
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1 This work was supported in part by grants from the American Society of Transplantation Basic Science Physician Scientist Award (to P.H.H.), Roche Organ Transplantation Research Foundation (to G.L.B.), the American Society of Transplant Surgeons (to G.L.B.), and National Institutes of Health DK072262 (to G.L.B.).
2 Address correspondence and reprint requests to Dr. Ginny L. Bumgardner, Ohio State University Medical Center, Department of Surgery, Division of Transplant, 1654 Upham Drive, 373 Means Hall, Columbus, OH 43210-1250. E-mail address: ginny.bumgardner{at}osumc.edu
3 Abbreviations used in this paper: KO, knockout; FasL, Fas ligand; GIC, graft-infiltrating cell; hA1AT, human 
-1 antitrypsin; MST, median survival time.
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