CD4+ T cell-associated pathophysiology critically depends on CD18 gene dose effects in a murine model of psoriasis

D Kess, T Peters, J Zamek, C Wickenhauser… - The Journal of …, 2003 - journals.aai.org
D Kess, T Peters, J Zamek, C Wickenhauser, S Tawadros, K Loser, G Varga, S Grabbe
The Journal of Immunology, 2003journals.aai.org
In a CD18 hypomorphic polygenic PL/J mouse model, the severe reduction of CD18 (β 2
integrin) to 2–16% of wild-type levels leads to the development of a psoriasiform skin
disease. In this study, we analyzed the influence of reduced CD18 gene expression on T cell
function, and its contribution to the pathogenesis of this disease. Both CD4+ and CD8+ T
cells were significantly increased in the skin of affected CD18 hypomorphic mice. But only
depletion of CD4+ T cells, and not the removal of CD8+ T cells, resulted in a complete …
Abstract
In a CD18 hypomorphic polygenic PL/J mouse model, the severe reduction of CD18 (β 2 integrin) to 2–16% of wild-type levels leads to the development of a psoriasiform skin disease. In this study, we analyzed the influence of reduced CD18 gene expression on T cell function, and its contribution to the pathogenesis of this disease. Both CD4+ and CD8+ T cells were significantly increased in the skin of affected CD18 hypomorphic mice. But only depletion of CD4+ T cells, and not the removal of CD8+ T cells, resulted in a complete clearance of the psoriasiform dermatitis. This indicates a central role of CD4+ T cells in the pathogenesis of this disorder, further supported by the detection of several Th1-like cytokines released predominantly by CD4+ T cells. In contrast to the CD18 hypomorphic mice, CD18 null mutants of the same strain did not develop the psoriasiform dermatitis. This is in part due to a lack of T cell emigration from dermal blood vessels, as experimental allergic contact dermatitis could be induced in CD18 hypomorphic and wild-type mice, but not in CD18 null mutants. Hence, 2–16% of CD18 gene expression is obviously sufficient for T cell emigration driving the inflammatory phenotype in CD18 hypomorphic mice. Our data suggest that the pathogenic involvement of CD4+ T cells depends on a gene dose effect with a reduced expression of the CD18 protein in PL/J mice. This murine inflammatory skin model may also have relevance for human polygenic inflammatory diseases.
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