Functional role of P-selectin glycoprotein ligand 1/P-selectin interaction in the generation of tolerogenic dendritic cells.
Dendritic cells (DCs) have a key role in both the generation of the immune response and the induction of tolerance to self-Ags. In this work, the possible role of P-selectin glycoprotein ligand 1 (PSGL-1) on the tolerogenic activity of human DCs was explored. We found that the engagement of PSGL-1 by P-selectin on DCs induced the expression of c-Fos, IDO, IL-10, and TGF-beta genes. Remarkably, stimulation of DCs through PSGL-1 with P-selectin enhanced their capability to generate CD4(+)CD25(+)Foxp3(+) regulatory T cells, which expressed high levels of TGF-beta1 mRNA, synthesized IL-10, and suppressed the proliferation of autologous CD4(+)CD25(-) T cells. Accordingly, we found that DCs from PSGL-1(-/-) mice expressed higher levels of MHC class II molecules, and exhibited an enhanced immunogenicity compared with wild-type mice. In addition, the percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells in the thymus of PSGL-1-deficient animals was significantly reduced. Our data reveal an unexpected role of PSGL-1 on the tolerogenic function of DCs, and the regulation of the immune response.
Urzainqui
Ana
A
Servicio de Inmunología, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Martínez del Hoyo
Gloria
G
Lamana
Amalia
A
de la Fuente
Hortensia
H
Barreiro
Olga
O
Olazabal
Isabel M
IM
Martin
Pilar
P
Wild
Martin K
MK
Vestweber
Dietmar
D
González-Amaro
Roberto
R
Sánchez-Madrid
Francisco
F
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics; D007108:Immune Tolerance / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10