CD25+CD4+ regulatory T cell migration requires L-selectin expression:: L-selectin transcriptional regulation balances constitutive receptor turnover

The molecular mechanisms controlling regulatory CD25(+)Foxp3(+)CD4(+) T cell (T-reg) migration are central to in vivo immune responses. T-reg cell subsets differentially express L-selectin, an adhesion molecule mediating lymphocyte migration to peripheral LNs (PLNs) and leukocyte rolling during inflammation. In this study, L-selectin was essential for T-reg cell migration and normal tissue distribution. Specifically, there was a 90% reduction in PLN T-reg cells in L-selectin(-/-) mice with a compensatory increase in spleen T-reg cell numbers. Unexpectedly, however, 40% of the CD4(+) T cells remaining within PLNs of L-selectin(-/-) mice were Treg cells. The migratory properties of T,,g cells were nonetheless markedly different from those of naive CD4(+) T cells, with 3- to 9-fold lower migration of T-reg cells into PLNs and similar to 2-fold lower migration into the spleen. T-reg cells also turned over cell surface L-selectin at a faster rate than CD25(-)CD4(+) T cells, but maintained physiologically appropriate L-selectin densities for optimal migration. Specifically, T-reg cells expressed 30-40% more cell surface L-selectin when its endoproteolytic cleavage was blocked genetically, which resulted in a 2-fold increase in T-reg M cell migration into PLNs. However, increased L-selectin cleavage by T-reg cells in wild-type mice was accompanied by 2-fold higher L-selectin mRNA levels, which resulted in equivalent cell surface L-selectin densities on T-reg and naive T cells. Thus, T-reg cells and CD25-CD4+ T cells share similar requirements for L-selectin expression during migration, although additional molecular mechanisms constrain T-reg cell migration beyond what is required for naive CD4(+) T cell migration.