TGF-beta-dependent suppressive function of Tregs requires wild-type levels of CD18 in a mouse model of psoriasis.
Dysfunctional Tregs have been identified in individuals with psoriasis. However, their role in the pathogenesis of the disease remains unclear. Here we explored the effect of diminished CD18 (beta2 integrin) expression on the function of CD4+CD25+CD127(-) Tregs using the Cd18 hypomorphic (Cd18hypo) PL/J mouse model of psoriasis that closely resembles the human disease. We found that reduced CD18 expression impaired cell-cell contact between Tregs and DCs. This led to dysfunctional Tregs, which both failed to suppress the pathogenic T cells and promoted the onset and severity of the disease. This failure was TGF-beta-dependent, as Tregs derived from Cd18hypo PL/J mice had diminished TGF-beta1 expression. Adoptive transfer of Tregs expressing wild-type levels of CD18 into affected Cd18hypo PL/J mice resulted in a substantial improvement of the psoriasiform skin disease, which did not occur upon coinjection of the cells with TGF-beta-specific neutralizing antibody. Our data indicate a primary dysfunction of Cd18hypo Tregs, allowing subsequent hyperproliferation of pathogenic T cells in the Cd18hypo PL/J mouse model of psoriasis. This study may provide a step forward in our understanding of the unique role of CD18 expression levels in avoiding autoimmunity.
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
Honglin
H
Wang
Thorsten
T
Peters
Anca
A
Sindrilaru
Daniel
D
Kess
Tsvetelina
T
Oreshkova
Xue-Zhong
XZ
Yu
Anne Maria
AM
Seier
Heike
H
Schreiber
Meinhard
M
Wlaschek
Robert
R
Blakytny
Jan
J
Röhrbein
Guido
G
Schulz
Johannes M
JM
Weiss
Karin
K
Scharffetter-Kochanek
D019264:Adoptive Transfer; D000825:Animal Structures / Q000166:cytology / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D011565:Psoriasis / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D053773:Transforming Growth Factor beta1 / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D018821:CD18 Antigens; D053773:Transforming Growth Factor beta1