Murine thymic selection quantified using a unique method to capture deleted T cells

GL Stritesky, Y Xing, JR Erickson… - Proceedings of the …, 2013 - National Acad Sciences
GL Stritesky, Y Xing, JR Erickson, LA Kalekar, X Wang, DL Mueller, SC Jameson
Proceedings of the National Academy of Sciences, 2013National Acad Sciences
Thymic positive and negative selection events generate a T-cell repertoire that is MHC
restricted and self-tolerant. The number of T cells undergoing positive and negative
selection in normal mice has never been firmly established. We generated mice that lack the
proapoptotic molecule Bim (bcl2l11) together with a Nur77GFP transgene, which allowed
the identification and enumeration of T cells that would normally undergo clonal deletion.
Using this method, we report the striking observation that six times more cells undergo …
Thymic positive and negative selection events generate a T-cell repertoire that is MHC restricted and self-tolerant. The number of T cells undergoing positive and negative selection in normal mice has never been firmly established. We generated mice that lack the proapoptotic molecule Bim (bcl2l11) together with a Nur77GFP transgene, which allowed the identification and enumeration of T cells that would normally undergo clonal deletion. Using this method, we report the striking observation that six times more cells undergo negative selection than complete positive selection. Seventy-five percent of the negatively selected cells are deleted at the double positive stage in the thymic cortex, compared with 25% at the single positive stage in the medulla. The fact that more thymocytes are highly reactive to MHC than are weakly reactive is inconsistent with a random model of recognition and suggests that T-cell recognition is MHC biased. Furthermore, Bim−/− mice had an increased number of GFPhi cells in the peripheral lymphoid tissue and a corresponding increase in antigen experienced or anergic cell phenotype. Our data also show that the CD4+ T cells that are clonally deleted experienced only slightly stronger T-cell receptor signaling than those that developed into regulatory T cells.
National Acad Sciences