TY - JOUR T1 - Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. JF - Nat Immunol Y1 - 2012 A1 - Pobezinsky, Leonid A A1 - Angelov, Georgi S A1 - Tai, Xuguang A1 - Jeurling, Susanna A1 - Van Laethem, Francois A1 - Feigenbaum, Lionel A1 - Park, Jung-Hyun A1 - Singer, Alfred KW - Animals KW - Antigens, CD28 KW - Antigens, CD4 KW - Antigens, CD8 KW - Cell Differentiation KW - Clonal Deletion KW - Flow Cytometry KW - Immune Tolerance KW - Mice KW - Mice, Inbred BALB C KW - Mice, Inbred C57BL KW - Mice, Knockout KW - Mice, Transgenic KW - Receptors, Antigen, T-Cell KW - Signal Transduction KW - Thymocytes KW - Thymus Gland AB -

Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor αβ subtype (TCRαβ) that 'preferentially' migrated to the intestine, where they re-expressed CD8α and were sequestered as CD8αα(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8αα(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection.

VL - 13 IS - 6 U1 -

http://www.ncbi.nlm.nih.gov/pubmed/22544394?dopt=Abstract

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