Out-of-Sequence Signal 3 Paralyzes Primary CD4⁺ T-Cell-Dependent Immunity

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.