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* Department of Microbiology and Immunology and
Department of Physiology and Cell Biology, University of Nevada, Reno, NV 89557;
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702; and
Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455
Recently, our laboratory reported that secondary CD8+ T cell-mediated antitumor responses were impaired following successful initial antitumor responses using various immunotherapeutic approaches. Although immunotherapy stimulated significant increases in CD8+ T cell numbers, the number of CD4+ T cells remained unchanged. The current investigation revealed a marked differential expansion of CD4+ T cell subsets. Successful immunotherapy surprisingly resulted in an expansion of CD4+Foxp3+ regulatory T (Treg) cells concurrent with a reduction of conventional CD4+ T (Tconv) cells, despite the marked antitumor responses. Following immunotherapy, we observed differential up-regulation of PD-1 on the surface of CD4+Foxp3+ Treg cells and CD4+Foxp3– Tconv cells. Interestingly, it was the ligand for PD-1, B7-H1 (PDL-1), that correlated with Tconv cell loss after treatment. Furthermore, IFN-
knockout (IFN-–/–) and IFN- receptor knockout (IFN-R–/–) animals lost up-regulation of surface B7-H1 even though PD-1 expression of Tconv cells was not changed, and this correlated with CD4+ Tconv cell increases. These results suggest that subset-specific expansion may contribute to marked shifts in the composition of the T cell compartment, potentially influencing the effectiveness of some immunotherapeutic approaches that rely on IFN-.
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 Grants R01 A134495, R01 CA72669, R37 HL56067, P01 AI0562991, P20 RR-016464, and R01 CA095572.
2 W.J.M, D.R, L.A.W, B.R.B, and R.W.H contributed research design and experimental oversight as well as data interpretation and help with writing the manuscript. K.L.A, Q.Z., V.B., D.E.C.W, and J.M.W. conducted experiments as well as helped with data analysis and writing the manuscript.
3 Address correspondence and reprint requests to Dr. William J. Murphy, University of Nevada, ARF Room 342, Mail Stop 199, Reno, NV 89557. E-mail address: wmurphy{at}medicine.nevada.edu
4 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; PD-1, programmed death-1; Tconv, conventional T; Treg, regulatory T.
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  Q. Gao, X.-Y. Wang, S.-J. Qiu, I. Yamato, M. Sho, Y. Nakajima, J. Zhou, B.-Z. Li, Y.-H. Shi, Y.-S. Xiao, et al. Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma Clin. Cancer Res., February 1, 2009; 15(3): 971 - 979. [Abstract] [Full Text] [PDF]
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