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

•Pre-exposure to elevated cytokines impairs TCR-mediated activation in CD4+ T cells•Cytokines directly induce Socs3, suppressing IL-2 signaling and proliferation•Contact with antigen during paralysis inhibits CD4+ T cell help and memory responses•Paralysis can protect from potential autoimmunity during systemic inflammation

SummaryPrimary 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.

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