期刊
JOURNAL OF IMMUNOLOGY
卷 183, 期 7, 页码 4284-4291出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0901408
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资金
- Fonds de la Recherche Scientifique
- Televie
- Wallonia Region
- GlaxoSmithKline Biologicals
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. The Journal of Immunology, 2009, 183: 4284-4291.
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