CD25+CD4+ Regulatory T Cell Migration Requires L-Selectin Expression: L-Selectin Transcriptional Regulation Balances Constitutive Receptor Turnover

Abstract

The molecular mechanisms controlling regulatory CD25+Foxp3+CD4+ T cell (Treg) migration are central to in vivo immune responses. Treg 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 Treg cell migration and normal tissue distribution. Specifically, there was a 90% reduction in PLN Treg cells in L-selectin−/− mice with a compensatory increase in spleen Treg cell numbers. Unexpectedly, however, 40% of the CD4+ T cells remaining within PLNs of L-selectin−/− mice were Treg cells. The migratory properties of Treg cells were nonetheless markedly different from those of naive CD4+ T cells, with 3- to 9-fold lower migration of Treg cells into PLNs and ∼2-fold lower migration into the spleen. Treg 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, Treg cells expressed 30–40% more cell surface L-selectin when its endoproteolytic cleavage was blocked genetically, which resulted in a 2-fold increase in Treg cell migration into PLNs. However, increased L-selectin cleavage by Treg 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 Treg and naive T cells. Thus, Treg cells and CD25−CD4+ T cells share similar requirements for L-selectin expression during migration, although additional molecular mechanisms constrain Treg cell migration beyond what is required for naive CD4+ T cell migration.