Down-Regulation of CD62L Shedding in T Cells by CD39+Regulatory T Cells Leads to Defective Sensitization in Contact Hypersensitivity Reactions.
Injection of regulatory T cells (Tregs) followed by sensitization with 2,4,6-trinitrochlorobenzene induced a transient increase in size and cellularity of skin-draining lymph nodes (LNs) in mice. This led us to hypothesize that Tregs may affect the trafficking of T cells from and to peripheral LNs. Two to three hours after sensitization, we found fewer CD8+T cells expressing CD62L in LNs compared with untreated controls. Injection of wild-type Tregs prevented this down-regulation of CD62L. In contrast, Tregs devoid of the adenosine triphosphate (ATP)-degrading ecto-enzyme CD39 were unable to do so. As for the mechanism of CD62L regulation, we found that ATP, which is released in skin upon hapten-exposure, is inducing the protease ADAM17 in LN-residing T cells via engagement of P2X7ATP receptors. ADAM17 cleaves CD62L from the surface of CD8+T cells, which in turn provide a signal for T cells to leave the LNs. This regulation of CD62L is disturbed by the presence of Tregs, because Tregs remove extracellular ATP from the tissue by activity of CD39 and, therefore, abrogate the shedding of CD62L. Thus, these data indicate that the regulation of ATP turnover by Tregs in skin and LNs is an important modulator for immune responses.
Ruprecht-Karls-University Heidelberg, Department of Dermatology, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany. Electronic address: karsten.mahnke@med.uni-heidelberg.de.
Karsten
K
Mahnke
Ruprecht-Karls-University Heidelberg, Department of Dermatology, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany; Centre of Dermatovenereology, Vilnius University Hospital Santariskiu klinikos, Vilnius, Lithuania.
Jurgina
J
Useliene
Ruprecht-Karls-University Heidelberg, Department of Dermatology, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.
Sabine
S
Ring
Ruprecht-Karls-University Heidelberg, Department of Dermatology, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.
Paula
P
Kage
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, University Hospital, Essen, Germany.
Verena
V
Jendrossek
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Simon C
SC
Robson
Centre of Dermatovenereology, Vilnius University Hospital Santariskiu klinikos, Vilnius, Lithuania.
Matilda
M
Bylaite-Bucinskiene
Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
Kerstin
K
Steinbrink
Ruprecht-Karls-University Heidelberg, Department of Dermatology, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany.
Alexander H
AH
Enk
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001081:Apyrase / Q000276:immunology*; D015153:Blotting, Western; D002478:Cells, Cultured; D017449:Dermatitis, Allergic Contact / Q000276:immunology*; D015536:Down-Regulation; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D007114:Immunization / Q000379:methods*; D007155:Immunologic Factors / Q000378:metabolism; D019041:L-Selectin / Q000187:drug effects / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012016:Reference Values; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D007155:Immunologic Factors; D019041:L-Selectin; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen