CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells

Area of Science:

• Immunology
• Cell Biology

Background:

• Interleukin-9 (IL-9)-producing T helper type 9 (Th9) cells have demonstrated both pro- and anti-inflammatory roles in inflammatory bowel diseases (IBDs).
• Functional heterogeneity within Th9 cells necessitates detailed investigation into their specific expression patterns and diversity.

Purpose of the Study:

• To dissect the expression patterns and diversity of antigen-specific murine Th9 cells.
• To investigate the role of CD96 (Cluster of Differentiation 96) in regulating Th9 cell function and inflammatory potential.

Main Methods:

• Single-cell transcription profiling of murine Th9 cells.
• Comparative analysis of CD96 expression across different T helper subsets.
• In vivo transfer of distinct Th9 cell subsets into recombination activating gene 1-deficient (Rag1-/-) mice.
• Assessment of inflammatory potential, expansion, and migratory capacity of Th9 cells.
• Evaluation of CD96 blockade on Th9 cell function.

Main Results:

• Th9 cells exhibit unique expression profiles, with reduced CD40 ligand and CD96, and increased CD25 and CD83 compared to other T helper subsets.
• Two distinct Th9 cell subsets were identified based on CD96 expression: CD96-low and CD96-high.
• CD96-low Th9 cells demonstrated potent inflammatory potential, causing severe weight loss and intestinal inflammation in recipient mice.
• CD96-high Th9 cells showed reduced expansion and migratory capacity, with no induction of colitis.
• CD96 blockade restored the inflammatory properties of CD96-high Th9 cells.

Conclusions:

• CD96 acts as an inhibitory cosignaling receptor in Th9 cells, modulating their inflammatory potential.
• The differential expression of CD96 defines functionally distinct Th9 cell subsets.
• Targeting CD96 offers a promising therapeutic strategy for treating IL-9-associated inflammatory conditions, including IBD.