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 nave 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, induction of autoimmunity, as well as impaired viral clearance. These data highlight the critical regulation of nave CD4+ T cells during inflammatory conditions.

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Sckisel GD, Bouchlaka MN, Monjazeb AM, Crittenden M, Curti BD, Wilkins DE, Alderson KA, Sungur CM, Ames E, Mirsoian A, Reddy A, Alexander W, Soulika A, Blazar BR, Longo DL, Wiltrout RH, Murphy WJ