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 T(reg) cells. The migratory properties of T(reg) 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 approximately 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) 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.