Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo.
Regulatory T cells (Tregs) play a fundamental role in the suppression of different immune responses; however, compartments at which they exert suppressive functions in vivo are unknown. Although many groups have described the presence of Tregs within inflammatory sites, it has not been shown that inflamed tissues are, indeed, the sites of active suppression of ongoing immune reactions. Here, by using alpha(E)+ effector/memory-like Tregs from fucosyltransferase VII-deficient animals, which lack E/P-selectin ligands and fail to migrate into inflamed sites, we analyzed the functional importance of appropriate Treg localization for in vivo suppressive capacity in an inflammation model. Lack of suppression by Tregs deficient in E/P-selectin ligands demonstrates that immigration into inflamed sites is a prerequisite for the resolution of inflammatory reactions in vivo because these selectin ligands merely regulate entry into inflamed tissues. In contrast, control of proliferation of naive CD4+ T cells during the induction phase of the immune response is more efficiently exerted by the naive-like alpha(E)-CD25+ Treg subset preferentially recirculating through lymph nodes when compared with its inflammation-seeking counterpart. Together, these findings provide the first conclusive evidence that appropriate localization is crucial for in vivo activity of Tregs and might have significant implications for anti-inflammatory therapies targeting recruitment mechanisms.
Siegmund
Kerstin
K
Experimentelle Rheumatologie, Charité Universit-aetsmedizin Berlin, c/o DRFZ, Schumannstr 21/22, 10117 Berlin, Germany.
Feuerer
Markus
M
Siewert
Christiane
C
Ghani
Saeed
S
Haubold
Uta
U
Dankof
Anja
A
Krenn
Veit
V
Schön
Michael P
MP
Scheffold
Alexander
A
Lowe
John B
JB
Hamann
Alf
A
Syrbe
Uta
U
Huehn
Jochen
J
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D012871:Skin Diseases / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D015704:CD4 Antigens; D015375:Receptors, Interleukin-2