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CD4⁺CD25^– T Cells Transduced to Express MHC Class I-Restricted Epitope-Specific TCR Synthesize Th1 Cytokines and Exhibit MHC Class I-Restricted Cytolytic Effector Function in a Human Melanoma Model¹

Arvind Chhabra^2,*, Lili Yang, Pin Wang, Begoña Comin-Anduix^¶, Raja Das^*, Nitya G. Chakraborty^*, Swagatam Ray^*, Shikhar Mehrotra^||, Haiguang Yang, Cinnamon L. Hardee, Roger Hollis, David I. Dorsky^*, Richard Koya^¶, Donald B. Kohn, Antoni Ribas^¶, James S. Economou^¶, David Baltimore and Bijay Mukherji^2,*

^* Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030; Division of Biology, California Institute of Technology, Pasadena, CA 91125; University of Southern California, Los Angeles, CA 90089; Children’s Hospital Los Angeles, Los Angeles, CA 90027; ^¶ Department of Medicine and Surgery, University of California, Los Angeles, CA 90095; and ^|| Department of Surgery, Medical University of South Carolina, Charleston, SC 29425

Cytolytic T cell-centric active specific and adoptive immunotherapeutic approaches might benefit from the simultaneous engagement of CD4⁺ T cells. Considering the difficulties in simultaneously engaging CD4⁺ and CD8⁺ T cells in tumor immunotherapy, especially in an Ag-specific manner, redirecting CD4⁺ T cells to MHC class I-restricted epitopes through engineered expression of MHC class I-restricted epitope-specific TCRs in CD4⁺ T cells has emerged as a strategic consideration. Such TCR-engineered CD4⁺ T cells have been shown to be capable of synthesizing cytokines as well as lysing target cells. We have conducted a critical examination of functional characteristics of CD4⁺ T cells engineered to express the - and β-chains of a high functional avidity TCR specific for the melanoma epitope, MART-1_27–35, as a prototypic human tumor Ag system. We found that unpolarized CD4⁺CD25^– T cells engineered to express the MART-1_27–35 TCR selectively synthesize Th1 cytokines and exhibit a potent Ag-specific lytic granule exocytosis-mediated cytolytic effector function of comparable efficacy to that of CD8⁺ CTL. Such TCR engineered CD4⁺ T cells, therefore, might be useful in clinical immunotherapy.

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 Public Health Service Grants CA 83130 (to B.M.), CA 88059 (to B.M.), CA129816 (to J.S.E.), grants from the Dowling Foundation (to B.M.), General Clinical Research Grant MO1RR06192 (to University of Connecticut Health Center), Samuel Waxman Foundation, and WM Keck Foundation (to J.S.E. for UCLA-CALTECH-CHLA-USC-UCONN Consortium on Translational Program in Engineered Immunity).

² Address correspondence and reprint requests to Dr. Arvind Chhabra and Dr. Bijay Mukherji, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030. E-mail addresses: arvindac{at}yahoo.com and mukherji{at}NSO2.uchc.edu

³ Abbreviations used in this paper: M1, Melan-A/MART-1_27–35; M14.2, V 2.2/Vβ14.