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

Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4679-84. doi: 10.1073/pnas.1217532110. Epub 2013 Mar 4.

Abstract

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 Nur77(GFP) 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 GFP(hi) 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.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • Bcl-2-Like Protein 11
  • Clonal Deletion / physiology*
  • Histocompatibility Antigens / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Mice, Knockout
  • Models, Immunological*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / immunology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Thymus Gland / immunology*

Substances

  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Histocompatibility Antigens
  • Membrane Proteins
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Proto-Oncogene Proteins