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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901408v1 183/7/4284    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Rivas, M. N. Articles by Braun, M. Y. PubMed PubMed Citation Articles by Rivas, M. N. Articles by Braun, M. Y.

Reviving Function in CD4⁺ T Cells Adapted to Persistent Systemic Antigen¹

Magali Noval Rivas^*, Kathleen Weatherly^*, Marc Hazzan^*, Benoit Vokaer^*, Sarah Dremier^*, Florence Gaudray^*, Michel Goldman^*, Isabelle Salmon and Michel Y. Braun^2,*

^* Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium; and Laboratory of Pathology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium

In bone marrow-transplanted patients, chronic graft-versus-host disease is a complication that results from the persistent stimulation of recipient minor histocompatibility Ag (mHA)-specific T cells contained within the graft. In this study, we developed a mouse model where persistent stimulation of donor T cells by recipient’s mHA led to multiorgan T cell infiltration. Exposure to systemic mHA, however, deeply modified T cell function and chronically stimulated T cells developed a long-lasting state of unresponsiveness, or immune adaptation, characterized by their inability to mediate organ immune damages in vivo. However, analysis of the gene expression profile of adapted CD4⁺ T cells revealed the specific coexpression of genes known to promote differentiation and function of Th1 effector cells as well as genes coding for proteins that control T cell activity, such as cell surface-negative costimulatory molecules and regulatory cytokines. Strikingly, blockade of negative costimulation abolished T cell adaptation and stimulated strong IFN- production and severe multiorgan wasting disease. Negative costimulation was also shown to control lethal LPS-induced toxic shock in mice with adapted T cells, as well as the capacity of adapted T cells to reject skin graft. Our results demonstrate that negative costimulation is the molecular mechanism used by CD4⁺ T cells to adapt their activity in response to persistent antigenic stimulation. The effector function of CD4⁺ T cells that have adapted to chronic Ag presentation can be activated by stimuli strong enough to overcome regulatory signals delivered to the T cells by negative costimulation.

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 the Fonds de la Recherche Scientifique, the Télévie, the Wallonia Region, and GlaxoSmithKline Biologicals.

² Address correspondence and reprint requests to Dr. Michel Y. Braun, Institute for medical Immunology, Université Libre de Bruxelles, rue Adrienne Bolland 8, 6041, Gosselies, Belgium. E-mail address: mbraun{at}ulb.ac.be

³ Abbreviations used in this paper: mHA, minor histocompatibility Ag; GVHD, graft-versus-host disease; PD-1, programmed death 1; PD-L1, PD-1 ligand 1.

⁴ The online version of this article contains supplemental material.