Out-of-sequence signal 3 paralyzes primary CD4 T-Cell-dependent immunity
- Author(s)
- 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;
- Details
- Publication Year 2015-08-18,Volume 43,Issue #2,Page 240-50
- Journal Title
- Immunity
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- Cell Press
- Research Division(s)
- Cancer And Haematology
- PubMed ID
- 26231116
- Publisher's Version
- https://doi.org/10.1016/j.immuni.2015.06.023
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-08-21 12:29:33
Last Modified: 2015-09-02 01:53:44