Treg cells require Izumo1R to regulate γδT cell-driven inflammation in the skin

Area of Science:

• Immunology
• Cell Biology
• Dermatology

Background:

• Izumo1R, a pseudo-folate receptor, is known for its role in fertilization.
• It is also expressed in CD4+ T lymphocytes, specifically regulatory T cells (Tregs) controlled by Foxp3.
• The function of Izumo1R in Tregs remains largely unexplored.

Purpose of the Study:

• To investigate the role of Izumo1R in Treg cell function.
• To analyze the impact of Treg-specific Izumo1r deficiency on immune responses and skin inflammation.

Main Methods:

• Generation and analysis of Treg-specific Izumo1r-deficient mice (Iz1rTrKO).
• Assessment of Treg cell differentiation, homeostasis, and phenotypes (PD1+, CD44hi).
• Evaluation of susceptibility to imiquimod-induced skin disease and other inflammatory/tumor challenges.
• Analysis of skin inflammation and gamma delta (γδ) T cell populations in Iz1rTrKO mice.
• Immunostaining to detect Izumo1 expression in dermal γδT cells.

Main Results:

• Treg differentiation and homeostasis were largely normal in Iz1rTrKO mice.
• No overt autoimmunity was observed, with only minor increases in PD1+ and CD44hi Treg phenotypes.
• pTreg differentiation remained unaffected.
• Iz1rTrKO mice showed unique susceptibility to imiquimod-induced, γδT cell-dependent skin disease.
• Subclinical inflammation and an imbalance of Rorγ+ γδT cells were noted in Iz1rTrKO mouse skin.
• Normal mouse skin revealed Izumo1 expression selectively in dermal γδT cells.

Conclusions:

• Izumo1R plays a significant role in Treg-mediated control of a specific pathway of skin inflammation.
• The interaction between Izumo1R on Tregs and Izumo1 on γδT cells is proposed to be critical for this regulation.
• Treg-specific Izumo1r deficiency predisposes to γδT cell-driven skin inflammation.