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Control of Memory CD4 T Cell Recall by the CD28/B7 Costimulatory Pathway¹

Modesta P. Ndejembi^*,, John R. Teijaro^*,, Deepa S. Patke^*, Adam W. Bingaman^2,*, Meena R. Chandok^*, Agnes Azimzadeh, Steven G. Nadler and Donna L. Farber^3,*

^* Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD 21201; Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; and Immunology and Inflammation Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543

The CD28/B7 costimulatory pathway is generally considered dispensable for memory T cell responses, largely based on in vitro studies demonstrating memory T cell activation in the absence of CD28 engagement by B7 ligands. However, the susceptibility of memory CD4 T cells, including central (CD62L^high) and effector memory (T_EM; CD62L^low) subsets, to inhibition of CD28-derived costimulation has not been closely examined. In this study, we demonstrate that inhibition of CD28/B7 costimulation with the B7-binding fusion molecule CTLA4Ig has profound and specific effects on secondary responses mediated by memory CD4 T cells generated by priming with Ag or infection with influenza virus. In vitro, CTLA4Ig substantially inhibits IL-2, but not IFN- production from heterogeneous memory CD4 T cells specific for influenza hemagglutinin or OVA in response to peptide challenge. Moreover, IL-2 production from polyclonal influenza-specific memory CD4 T cells in response to virus challenge was completely abrogated by CTLA4Ig with IFN- production partially inhibited. When administered in vivo, CTLA4Ig significantly blocks Ag-driven memory CD4 T cell proliferation and expansion, without affecting early recall and activation. Importantly, CTLA4Ig treatment in vivo induced a striking shift in the phenotype of the responding population from predominantly T_EM in control-treated mice to predominantly central memory T cells in CTLA4Ig-treated mice, suggesting biased effects of CTLA4Ig on T_EM responses. Our results identify a novel role for CD28/B7 as a regulator of memory T cell responses, and have important clinical implications for using CTLA4Ig to abrogate the pathologic consequences of T_EM cells in autoimmunity and chronic disease.

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 a grant from Bristol-Myers Squibb, and National Institutes of Health Grants AI50632 and AI42092 (awarded to D.L.F.).

² Current address: Department of Surgery, University of Texas, San Antonio, TX 78229.

³ Address correspondence and reprint requests to Dr. Donna L. Farber, University of Maryland, Baltimore, Department of Surgery, Medical School Teaching Facility, Room 400, 685 West Baltimore Street, Baltimore, MD 21201. E-mail address: dfarber{at}smail.umaryland.edu

⁴ Abbreviations used in this paper: T_CM, central memory T; HA, hemagglutinin; T_EM, effector memory T.

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