IL-2 signaling prevents T cell anergy by inhibiting the expression of anergy-inducing genes.
T cell responses are determined by the environment in which antigen is encountered. In the absence of proper costimulation, anergizing stimuli induce the activation of a specific program of gene expression. Proteins encoded by these genes impose a state of functional unresponsiveness in anergic T cells through the activation of different mechanisms that include dampening of the T cell receptor signaling and direct inhibition of cytokine expression. Anergy can be reversed by stimulating T cells in the presence of interleukin (IL-)2. Signaling through the IL-2 receptor has been shown to activate mTOR, which plays an important role in the integration of signals that determine the fate of T cells. The mechanisms underlying the IL-2-dependent regulation of T cell tolerance are still not fully elucidated. In this study we show that IL-2 receptor signaling mediated through JAK3 and mTOR inhibits the expression of anergy-inducing genes independently of any effect on cell cycle progression. Interestingly, we also show that this effect is likely due to changes on the levels of AP-1 activation induced by IL-2 receptor signaling in T cells. Our data identifies a mechanism that can explain how IL-2 may prevent or reverse the establishment of anergy in T cells and, therefore, helps to understand how the cytokine environment can be determinant to shape the outcome of T cell responses - tolerance or activation - when antigen is encountered.
Duré
Myrianne
M
Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Macian
Fernando
F
D000818:Animals; D002453:Cell Cycle / Q000276:immunology*; D017635:Clonal Anergy; D005786:Gene Expression Regulation / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology*; D053616:Janus Kinase 3 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011494:Protein Kinases / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases; D018808:Transcription Factor AP-1 / Q000276:immunology
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D018808:Transcription Factor AP-1; D011494:Protein Kinases; C546843:mTOR protein, mouse; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D058570:TOR Serine-Threonine Kinases