TGF-Beta–Dependent Suppressive Function of Tregs Requires Wild-Type Levels of CD18 in a Mouse Model of Psoriasis
Wang H, Peters T, Sindrilaru A, et al
J Clin Invest. 2008;118(7):2629-2639
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 C18 (beta2 integrin) expression on the function of CD4+CD25+CD127(−) Tregs using the Cd18 hypomorphic PL/J mouse model of psoriasis that closely resembles the human disease. We found that reduced C18 expression impaired cell-cell contact between Tregs and DCs [dendritic cells]. This led to dysfunction of 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 Cd18hypo PL/J mice resulted in 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 model of psoriasis. This study may provide a step forward in our understanding of the unique role of CD18 expression levels in avoiding autoimmunity.