Thymic Development of CD425 Foxp3 T-Regulatory Cells Echoes their Suppressogenic Capacity in Periphery

ABSTRACT

The CD4⁺25^hiFoxp3⁺ T regulatory (T-reg) cells are naturally-born in thymus and they are critical for maintaining 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-2d) haplotype, we found that Foxp3 is early expressed 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 Treg precursors, but not by epigenetic alterations at the Foxp3 gene promoter. Faster T-reg proliferation and lower apoptosis were associated with higher Foxp3⁺ thymic cell output. Also, faster proliferating T-reg precursors showed lower expression of CD3/TCR complex, leptin receptor, Bad, and Caspase3 early in the DN stage of differentiation. Despite a differential T-reg thymic output in these two mouse strains, the size of peripheral CD4⁺25^hiFoxp3⁺ 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.

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