Reduced Numbers of Mature Medullary Thymic Epithelial Cells in SKG Mice

Abstract

Attenuated T cell receptor (TCR) signalling contributes to the susceptibility for autoimmunity as shown via mutants of PTPN22 and Zap70 genes. We here set out to investigate the effect of an attenuated TCR signal on the composition of the thymic epithelial cell (TEC) compartment. To that extent, we combined flow cytometry and histology and compared the TEC subpopulations of Zap70 wild type with SKG mutant mice. We found an increased cortical TEC compartment in SKG thymi at the expense of reduced numbers of mature medullary TECs and a 4.8-fold reduced medulla area. We also found reduced proportions of CD69⁺ -activated thymocytes among double-negative, double-positive and CD4^- CD8⁺ single-positive stages, reduced absolute numbers of single-positive thymocytes, diminished expression of Lta and Ltb by CD4^- CD8⁺ single-positive thymocytes and a diminished expression of Ccl19, a target gene of the lymphotoxin-b-receptor. While the reduced thymocyte numbers together with the attenuated TCR signal explain the diminished expression of lymphotoxins, the latter is required for an AIRE-independent expression of tissue-restricted antigens as well as attracting positively selected thymocytes to the medulla. Our results describe altered TEC compartments in SKG mice that are likely to support the development of autoimmunity.