|Title||Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.|
|Publication Type||Journal Article|
|Year of Publication||2012|
|Authors||Pobezinsky, LA, Angelov, GS, Tai, X, Jeurling, S, Van Laethem, F, Feigenbaum, L, Park, J-H, Singer, A|
|Date Published||2012 Jun|
|Keywords||Animals, Antigens, CD28, Antigens, CD4, Antigens, CD8, Cell Differentiation, Clonal Deletion, Flow Cytometry, Immune Tolerance, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Receptors, Antigen, T-Cell, Signal Transduction, Thymocytes, Thymus Gland|
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.
|Alternate Journal||Nat. Immunol.|