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.
Venturi
Guglielmo M
GM
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Conway
Rochelle M
RM
Steeber
Douglas A
DA
Tedder
Thomas F
TF
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015704:CD4 Antigens / Q000032:analysis; D002465:Cell Movement / Q000235:genetics*; D005786:Gene Expression Regulation; D039001:Integrin alpha Chains / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D019041:L-Selectin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D011971:Receptors, Immunologic / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D014158:Transcription, Genetic
D015703:Antigens, CD; D015704:CD4 Antigens; D039001:Integrin alpha Chains; D053645:Interleukin-2 Receptor alpha Subunit; D011971:Receptors, Immunologic; C091367:alpha E integrins; D019041:L-Selectin