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

• Published in: The Journal of immunology (1950) 2009-10, Vol.183 (7), p.4284-4291
• Main Authors: Rivas, Magali Noval, Weatherly, Kathleen, Hazzan, Marc, Vokaer, Benoit, Dremier, Sarah, Gaudray, Florence, Goldman, Michel, Salmon, Isabelle, Braun, Michel Y
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigen Presentation - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - transplantation; Cells, Cultured; Female; H-Y Antigen - immunology; Immune Tolerance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Minor Histocompatibility Antigens - immunology; Molecular Sequence Data; Skin Transplantation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0901408

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-gamma 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.