The molecular signature of CD8(+) T cells undergoing deletional tolerance

Parish, IA; Rao, S; Smyth, GK; Juelich, T; Denyer, GS; Davey, GM; Strasser, A; Heath, WR

Author(s): Parish, IA; Rao, S; Smyth, GK; Juelich, T; Denyer, GS; Davey, GM; Strasser, A; Heath, WR;
Details: Publication Year 2009-05-07,Volume 113,Issue #19,Page 4575-4585
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: Peripheral tolerance induction is critical for the maintenance of self-tolerance and can be mediated by immunoregulatory T cells or by direct induction of T-cell anergy or deletion. Although the molecular processes underlying anergy have been extensively studied, little is known about the molecular basis for peripheral T-cell deletion. Here, we determined the gene expression signature of peripheral CD8(+) T cells undergoing deletional tolerance, relative to those undergoing immunogenic priming or lymphopenia-induced proliferation. From these data, we report the first detailed molecular signature of cells undergoing deletion. Consistent with defective cytolysis, these cells exhibited deficiencies in granzyme up-regulation. Furthermore, they showed antigen-driven Bcl-2 down-regulation and early up-regulation of the proapoptotic protein Bim, consistent with the requirement of this BH3-only protein for peripheral T-cell deletion. Bim up-regulation was paralleled by defective interleukin-7 receptor alpha (IL-7R alpha) chain reexpression, suggesting that Bim-dependent death may be triggered by loss of IL-7/IL-7R signaling. Finally, we observed parallels in molecular signatures between deletion and anergy, suggesting that these tolerance pathways may not be as molecularly distinct as previously surmised. (Blood. 2009;113:4575-4585)
Publisher: AMER SOC HEMATOLOGY
Keywords: ORPHAN STEROID-RECEPTOR; FAMILY-MEMBER BIM; PERIPHERAL TOLERANCE; CROSS-PRESENTATION; BCL-2 FAMILY; IN-VIVO; NEGATIVE SELECTION; VIRAL-INFECTION; CUTTING EDGE; SELF-ANTIGEN
Publisher's Version: https://doi.org/10.1182/blood-2008-10-185223
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2009-05-07 12:00:00