Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4+ T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4+ but not CD8+ T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4+ T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4+ T cells during inflammatory conditions. Current dogma holds that T cell activation requires three signals in sequence. Murphy and colleagues show that the order of these signals is essential; strong systemic cytokine pre-exposure results in a transient state of anergy in which CD4+ T cells are unable to respond to antigen.
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We would like to thank Monja Metcalf and Weihong Ma for excellent technical assistance with these studies. We would also like to thank Dr. Jonathan Weiss for helpful discussions with the manuscript. We would also like to thank Dr. Fu-Tong Liu for donating his OT-II Tg mouse colony, which was further propagated for studies in this manuscript. This work was funded by grants from the NIH (R01 CA 095572 and R01 CA 072669). Samples from patients undergoing systemic high-dose IL-2 therapy were part of a larger study evaluating combination of radiotherapy with systemic IL-2. This trial is supported in part by Prometheus Laboratories, Inc.