An alternative role for Foxp3 as an effector T cell regulator controlled through CD40

Area of Science:

• Immunology
• Autoimmunity
• Type 1 Diabetes Research

Background:

• Defining pathogenic effector T cells in autoimmunity remains challenging.
• CD4(+) T cells expressing CD40 (Th40 cells) are implicated in type 1 diabetes development in NOD mice.
• NOD.BDC2.5.TCR.Tg mice have abundant Th40 cells, but diabetes onset is paradoxically slow.

Purpose of the Study:

• To investigate the role of CD40 in pathogenic T cell development and function in type 1 diabetes.
• To explore the relationship between Foxp3 expression, CD40, and T cell effector function in diabetes pathogenesis.

Main Methods:

• Generation of BDC2.5.CD40(-/-) mice to assess CD40's role.
• Transfer of Th40 cells (Foxp3(+) and Foxp3(-)) from various mouse models into NOD.scid recipients.
• Analysis of cytokine production (IL-17, IFN-γ, IL-2) by Th40 cells based on Foxp3 expression.

Main Results:

• Regulatory T cells develop normally in BDC2.5.CD40(-/-) mice, but pathogenic effector cells are reduced.
• Foxp3(+) Th40 cells from prediabetic mice induce diabetes slowly, while Foxp3(-) Th40 cells induce it rapidly.
• Foxp3(+) Th40 cells produce IL-17, whereas Foxp3(-) Th40 cells produce IFN-γ and IL-2. CD40 deficiency prevents Th40 cells from losing Foxp3 and transferring disease.

Conclusions:

• CD40 signaling is crucial for the development of pathogenic effector Th40 cells that drive type 1 diabetes.
• Foxp3 expression on Th40 cells significantly impacts their pathogenic potential and cytokine profile, shifting from IL-17 production to IFN-γ/IL-2 production upon Foxp3 loss.
• These findings offer a new perspective on Foxp3 function in regulating effector T cell activity during autoimmune diabetes development.