TGF-β–dependent suppressive function of Tregs requires wild-type levels of CD18 in a mouse model of psoriasis
Honglin Wang, … , Johannes M. Weiss, Karin Scharffetter-Kochanek
Honglin Wang, … , Johannes M. Weiss, Karin Scharffetter-Kochanek
Published June 2, 2008
Citation Information: J Clin Invest. 2008;118(7):2629-2639. https://doi.org/10.1172/JCI34916.
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Research Article Dermatology

TGF-β–dependent suppressive function of Tregs requires wild-type levels of CD18 in a mouse model of psoriasis

Abstract

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 (β2 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-β–dependent, as Tregs derived from Cd18hypo PL/J mice had diminished TGF-β1 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-β–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.

Authors

Honglin Wang, Thorsten Peters, Anca Sindrilaru, Daniel Kess, Tsvetelina Oreshkova, Xue-Zhong Yu, Anne Maria Seier, Heike Schreiber, Meinhard Wlaschek, Robert Blakytny, Jan Röhrbein, Guido Schulz, Johannes M. Weiss, Karin Scharffetter-Kochanek

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Figure 2

CD4+CD25+CD127– Tregs are decreased in numbers in affected Cd18hypo PL/J mice.

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CD4+CD25+CD127– Tregs are decreased in numbers in affected Cd18hypo PL/J...
Lymphocytes were firstly gated for CD4+CD25+ T cells derived from spleens of either Cd18wt or Cd18hypo affected mice (A) and thereafter analyzed for CD127 expression (B). The percentage of CD127+ (top corner) and CD127– (bottom corner) T cells within CD4+CD25+ T cell gate is shown. The panel on the right shows isotype matched IgG control staining. (C) Percentage of CD4+CD25+CD127– T cells in thymus, blood, spleen, and DLNs of Cd18wt and affected Cd18hypo mice with psoriasiform skin disease (n = 6 for each genotype and organ). The experiment was done twice, the median is shown. (D) To investigate CD127 expression by CD25+ T cells in the skin of affected Cd18hypo mice, skin cryosections from Cd18wt and affected Cd18hypo mice were double stained with CD25–Alexa Fluor 488 (green) and CD127-PE (red). Cell nuclei (blue) were counterstained with DAPI (original magnification, ×20). Red cells indicate CD25–CD127+ T cells and green cells represent CD25+CD127– Tregs, while overlay (yellow) represents double-positive T cells. e, epidermis; d, dermis; h, hair follicle. The dotted line indicates the border between epidermis and dermis. (E) To quantify CD25+CD127+ or CD25+CD127– T cells in the skin of affected Cd18hypo and Cd18wt mice, the positively stained cells were counted. For all measurements, the median of specifically stained T cells counted in 15 high-power fields (HPFs) is presented (n = 5). *P < 0.05, **P < 0.01, using Student’s t test.