Clonal deletion and the fate of autoreactive thymocytes that survive negative selection

Nat Immunol. 2012 Apr 29;13(6):569-78. doi: 10.1038/ni.2292.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD28 Antigens / immunology
  • CD4 Antigens / immunology
  • CD8 Antigens / immunology
  • Cell Differentiation / immunology*
  • Clonal Deletion / immunology*
  • Flow Cytometry
  • Immune Tolerance / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / immunology*
  • Signal Transduction / immunology
  • Thymocytes / cytology
  • Thymocytes / immunology*
  • Thymus Gland / cytology
  • Thymus Gland / immunology*


  • CD28 Antigens
  • CD4 Antigens
  • CD8 Antigens
  • Receptors, Antigen, T-Cell