Out-of-Sequence Signal 3 Paralyzes Primary CD4<sup>+</sup> T-Cell-Dependent Immunity

Gail D. Sckisel, Myriam N. Bouchlaka, Arta M Monjazeb, Marka Crittenden, Brendan D. Curti, Danice E C Wilkins, Kory A. Alderson, Can M. Sungur, Erik Ames, Annie Mirsoian, Abhinav Reddy, Warren Alexander, Athena Soulika, Bruce R. Blazar, Dan L. Longo, Robert H. Wiltrout, William J Murphy

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


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<sup>+</sup> 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<sup>+</sup> but not CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells are unable to respond to antigen.

Original languageEnglish (US)
Article number3145
Pages (from-to)240-250
Number of pages11
Issue number2
StatePublished - Aug 18 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology


Dive into the research topics of 'Out-of-Sequence Signal 3 Paralyzes Primary CD4<sup>+</sup> T-Cell-Dependent Immunity'. Together they form a unique fingerprint.

Cite this