Rho-GTPase dependent leukocyte interaction generates pro-inflammatory thymic Tregs and causes arthritis

Area of Science:

• Immunology
• Molecular Biology
• Rheumatology

Background:

• Conditional mutation of GGTase-I in macrophages (GLC) activates Rho-GTPases, leading to arthritis in mice.
• Lymphocytes are essential for arthritis development in GLC mice, as indicated by Rag1 knockout alleviating symptoms.

Purpose of the Study:

• To investigate GLC-dependent alterations in adaptive immunity.
• To elucidate the role of macrophages in stimulating pro-inflammatory regulatory T cells (Tregs).

Main Methods:

• Isolation and characterization of CD4+ T cells from GLC mice (CD4+GLCs).
• Analysis of gene expression (Cdc42, Rac1, HOXA proteins) and cell surface markers (GARP, NRP1, IKZF2, FOXP3).
• Genetic manipulation (knockout of Cdc42, Rac1, RhoA) and pharmacological intervention (CTLA4 fusion protein).
• Assessment of T cell phenotype (Th1) and Treg origin (thymic vs. non-thymic).

Main Results:

• CD4+GLCs exhibit high Cdc42 and Rac1 expression, promoting migration and displaying a thymic Treg signature.
• Activation of the β-catenin/Lef1 axis in Tregs correlates with a pro-inflammatory Th1 phenotype and arthritis severity.
• Macrophage Cdc42 knockout alters CD4+ cell biology, inducing non-thymic Tregs; Rac1/RhoA knockout alleviates arthritis without affecting CD4+ cells.
• Disrupting macrophage-T cell interaction reduces inflammation and thymic Treg accumulation in lymph nodes.

Conclusions:

• Macrophages play a critical role in promoting the development of pro-inflammatory thymic Tregs.
• Rho-GTPase activation in macrophages is a key mechanism driving the arthritogenic phenotype of these Tregs.
• Targeting macrophage-T cell interactions offers a potential therapeutic strategy for arthritis.