Thymic Development of CD4+25hi Foxp3+ T-Regulatory Cells Echoes their Suppressogenic Capacity in Periphery

Abstract

The CD4 + 25 hi Foxp3 + T regulatory (T-reg) cells are naturally-born in thymus and they are critical for maintain- ing the tolerance to self and non-self antigens. Foxp3 is the master-regulatory gene of development and function of this cell subset. Using two mouse strains that share the same MHC class II (H-2 d ) haplotype, we found that Foxp3 is early ex- pressed in the CD3 + 4 - 8 - 25 +/- 44 - (DN3/4) double negative thymocytes. Furthermore, Foxp3 showed a differential kinetics of expression in the thymus of these two strains that were controlled through the rates of proliferation and apoptosis of T- reg precursors, but not by epigenetic alterations at the Foxp3 gene promoter. Faster T-reg proliferation and lower apopto- sis were associated with higher Foxp3 + thymic cell output. Also, faster proliferating T-reg precursors showed lower ex- pression of CD3/TCR complex, leptin receptor, Bad, and Caspase3 early in the DN stage of differentiation. Despite a dif- ferential T-reg thymic output in these two mouse strains, the size of peripheral CD4 + 25 hi Foxp3 + T-reg compartment was homeostatically normalized. However, the Foxp3 + T-reg suppression tested in an autoimmune mouse model for diabetes was stronger in mice with a higher T-reg thymic output. These findings demonstrate a differential thymic development and suppressive capacity of Foxp3 + T-reg cells in two genetic backgrounds regardless the MHC II haplotype. This raises the question of whether a differential suppressogenic capacity of the T-reg compartment may affect the susceptibility to autoimmune disorders in individuals from different ethnic groups.