Deficiency of the Src homology region 2 domain-containing phosphatase 1 (SHP-1) causes enrichment of CD4⁺CD25⁺ regulatory T cells

A subpopulation of T cells, named regulatory T cells (T_reg cells), has been shown to play a key role in tolerance and the prevention of autoimmunity. It is not known how changes in TCR signal strength during thymic T cell development affect the generation of a T_reg population. In this study, we took two different strategies to modulate the TCR signal strength: an intrinsic approach, where signaling was enhanced by the loss of a negative regulator, and an extrinsic approach, where signaling strength was altered through variations in the concentrations of the selecting peptide. The tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a known negative regulator of TCR-mediated signaling, motheaten mice, lacking expression of SHP-1, showed a 2- to 3-fold increase in the percentage of CD4⁺CD25⁺ T_reg cells within the CD4⁺ T cells. Similarly, the percentage of T_reg cells was heightened in fetal thymic organ cultures (FTOCs) derived from motheaten mice compared with wild-type FTOCs, thus establishing the thymic origin of these T_reg cells. Using FTOCs derived from DO11.10 TCR transgenic mice, we demonstrated that exposure to increasing concentrations of the cognate OVA peptide favored the appearance of T_reg cells. Our data suggest that the development of CD4⁺CD25⁺ T_reg cells is intrinsically different from non-T_reg cells and that T_reg cells are selectively enriched under conditions of enhanced negative selection. Our data also reveal a key role for the SHP-1-mediated regulation of TCR signal strength in influencing the ratio of T_reg vs non-T_reg cells.