Impaired Treg-DC interactions contribute to autoimmunity in leukocyte adhesion deficiency 1

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common beta-chain of the beta 2-integrin family (CD18). The most prominent clinical symptoms are profound leukocytosis and high susceptibility to infections. Patients with LAD-1 are prone to develop autoimmune diseases, but the molecular and cellular mechanisms that result in coexisting immunodeficiency and autoimmunity are still unresolved. CD4+FOXP3+ Treg are known for their essential role in preventing autoimmunity. To understand the role of Treg in LAD-1 development and manifestation of autoimmunity, we generated mice specifically lacking CD18 on Treg (CD18Foxp3), resulting in defective LFA-1 expression. Here, we demonstrate a crucial role of LFA-1 on Treg to maintain immune homeostasis by modifying T cell-DC interactions and CD4+ T cell activation. Treg-specific CD18 deletion did not impair Treg migration into extralymphatic organs, but it resulted in shorter interactions of Treg with DC. In vivo, CD18Foxp3 mice developed spontaneous hyperplasia in lymphatic organs and diffuse inflammation of the skin and in multiple internal organs. Thus, LFA-1 on Treg is required for the maintenance of immune homeostasis.

Automated summary

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare disease characterized by leukocytosis and high susceptibility to infections. In this study, mice lacking CD18 specifically on regulatory T cells (Treg) were generated to investigate the role of Treg in LAD-1 and autoimmunity. The results demonstrate that LFA-1 on Treg plays a crucial role in maintaining immune homeostasis.