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Costimulation Modulation Uncouples Protection from Immunopathology in Memory T Cell Responses to Influenza Virus¹

John R. Teijaro^*, Modesta N. Njau^*, David Verhoeven^*, Smita Chandran^*, Steven G. Nadler, Jeffrey Hasday and Donna L. Farber^2,*

^* Department of Surgery and Department of Medicine, 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 rapid effector functions and tissue heterogeneity of memory T cells facilitate protective immunity, but they can also promote immunopathology in antiviral immunity, autoimmunity, and transplantation. Modulation of memory T cells is a promising but not yet achieved strategy for inhibiting these deleterious effects. Using an influenza infection model, we demonstrate that memory CD4 T cell-driven secondary responses to influenza challenge result in improved viral clearance yet do not prevent the morbidity associated with viral infection, and they exacerbate cellular recruitment into the lung, compared with primary responses. Inhibiting CD28 costimulation with the approved immunomodulator CTLA4Ig suppressed primary responses in naive mice infected with influenza, but was remarkably curative for memory CD4 T cell-mediated secondary responses to influenza, with reduced immunopathology and enhanced recovery. We demonstrate that CTLA4Ig differentially affects lymphoid and nonlymphoid responses to influenza challenge, inhibiting proliferation and egress of lymphoid naive and memory T cells, while leaving lung-resident memory CD4 T cell responses intact. Our findings reveal the dual nature of memory T cell-mediated secondary responses and suggest costimulation modulation as a novel strategy to optimize antiviral immunity by limiting the memory T cell response to its protective capacities.

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 project was supported by National Institutes of Health Grants AI50632 and AI077029 and by a grant from Bristol-Myers Squibb awarded to D.L.F.

² Address correspondence and reprint requests to Dr. Donna L. Farber, Department of Surgery, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201. E-mail address: dfarber{at}smail.umaryland.edu

³ Abbreviations used in this paper: HA, hemagglutinin; BAL, bronchoalveolar lavage; TCID₅₀, tissue culture infectious dose 50%.

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