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T Helper Lymphocytes Rescue CTL from Activation-Induced Cell Death¹

Richard Kennedy^* and Esteban Celis^2,

^* Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905; and H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology, University of South Florida, Tampa FL 33612

T cell activation is characterized by a vast expansion of Ag-specific T cells followed by an equally extensive reduction in T cell numbers. This decline is due, in part, to activation-induced apoptosis of the responding T cells during repeated encounter with Ag. In the current study, we used solid-phase MHC class I/peptide monomers to cause activation-induced cell death (AICD) of previously activated CD8 T cells in an Ag-specific manner. AICD occurred rapidly and was mediated primarily by Fas–FasL interactions. Most interestingly, we observed that Th cells could provide survival signals to CTL significantly reducing the level of AICD. Both Th1 and Th2 subsets were capable of protecting CTL from AICD, and a major role for soluble factors in this protection was ruled out, as cell-to-cell contact was an essential component of this Th-mediated protection. Upon encounter with Ag-expressing tumor cells, CTL underwent significant apoptosis. However, in the presence of Th cells, the CTL not only were protected against death, but also had significantly greater lytic ability. In vivo tumor protection studies using peptide immunization showed that the activation of Ag-specific Th cells was crucial for optimal protection, but did not affect the magnitude of the CTL response in the lymphoid tissues. In this study, we examine the type of help that CD4 T cells may provide and propose a model of Th cell–CTL interaction that reduces CTL death. Our results show a novel role for Th cells in the maintenance of CTL responses.

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 in part by National Institutes of Health Grants P50CA91956, T32AI07425, R01CA103921, and R01CA80782.

² Address correspondence and reprint requests to Dr. Esteban Celis, H. Lee Moffitt Cancer Center, University of South Florida, Mail Stop SRB-2, 12902 Magnolia Drive, Tampa FL 33612. E-mail address: ecelis{at}moffitt.usf.edu

³ Abbreviations used in this paper: MHC-I, MHC class I; AICD, activation-induced cell death; KO, knockout; rhIL-2, recombinant human IL-2; 7-AAD, 7-aminoactinomycin D; L-NMMA, NG-methyl-L-arginine; NAC, N-acetyl-L-cysteine; CI, caspase inhibitor; wt, wild type; AINR, Ag-induced nonresponsiveness; PADRE, pan HLA DR-binding epitope.

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