Impaired Treg-DC interactions contribute to autoimmunity in leukocyte adhesion deficiency type 1
Tanja Klaus, … , Tobias Bopp, Stephan Grabbe
Tanja Klaus, … , Tobias Bopp, Stephan Grabbe
Published November 8, 2022
Citation Information: JCI Insight. 2022;7(24):e162580. https://doi.org/10.1172/jci.insight.162580.
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Research Article

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

Abstract

Leukocyte adhesion deficiency type 1 (LAD-1) is a rare disease resulting from mutations in the gene encoding for the common β-chain of the β2-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.

Authors

Tanja Klaus, Alicia S. Wilson, Elisabeth Vicari, Eva Hadaschik, Matthias Klein, Sara Salome Clara Helbich, Nadine Kamenjarin, Katrin Hodapp, Jenny Schunke, Maximilian Haist, Florian Butsch, Hans Christian Probst, Alexander H. Enk, Karsten Mahnke, Ari Waisman, Monika Bednarczyk, Matthias Bros, Tobias Bopp, Stephan Grabbe

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Figure 5

Treg-specific deletion of CD18 does not impair tissue homing of cells.

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Treg-specific deletion of CD18 does not impair tissue homing of cells. (...
(A) Immunofluorescence images of Treg infiltration in ears of 17- to 20-week-old mice showing nuclei marked with DAPI and Treg identified by FOXP3 expression. Images representative of 3 mice per group. Magnification, 40×. (B) Quantification of total number of FOXP3+ Treg per field of view from immunofluorescence imaging of ears of WT and CD18Foxp3 mice; n = 3–4. (C and D) Representative flow cytometry plots of FOXP3 expression on splenic CD4 T cells, and quantification of Treg frequencies as a percentage of total CD3+ T cells in various organs of 12- to 13-week-old mice; n = 3–6. (E) Quantification of surface expression of CD62L on FOXP3+ Treg from multiple organs measured by flow cytometry; n = 4–8. (F) Expression of Sell and Selp transcripts by unstimulated and stimulated CD18-sufficient and -deficient Treg; n = 3. (G and H) Surface expression of proteins involved in cell adhesion on CD18wt and CD18Foxp3 Treg from blood, spleen, skin draining lymph node (sdLN), and lungs of mice; n = 3–4. (B, D, E, G, and H) Dots represent individual mice. Data are shown as mean ± SEM, representative of at least 2 independent experiments. Significance was determined by 2-tailed unpaired t test (B) or 2-way ANOVA with Šídák’s multiple-comparison test (D–H). *P < 0.05; **P < 0.01; ***P < 0.001; ****P ≤ 0.0001. e, epidermis; d, dermis.