The LEF1-LAG3 axis regulates CD4⁺ T cell function during Plasmodium yoelii NSM infection.

Area of Science:

• Immunology
• Parasitology
• Molecular Biology

Background:

• CD4⁺ T cells are crucial for anti-malarial immunity.
• Lymphocyte-activation gene 3 (LAG3) is a co-inhibitory receptor that regulates T cell function.
• The role and regulation of LAG3⁺CD4⁺ T cells in Plasmodium infection are not fully understood.

Purpose of the Study:

• To investigate the phenotype and function of LAG3⁺CD4⁺ T cells during Plasmodium infection.
• To elucidate the upstream molecular mechanisms regulating LAG3 expression on CD4⁺ T cells.

Main Methods:

• Murine model of Plasmodium yoelii NSM infection.
• Single-cell RNA sequencing (scRNA-seq) and flow cytometry.
• Quantitative PCR, luciferase reporter assays, and in vitro Wnt pathway modulation.

Main Results:

• Plasmodium infection led to splenomegaly and altered splenic CD4⁺ T cell populations, with increased LAG3 expression.
• LAG3⁺CD4⁺ T cells displayed an activated phenotype with enhanced proliferation and co-inhibitory receptor expression.
• Lymphoid enhancer-binding factor 1 (LEF1) directly repressed Lag3 transcription, and Wnt pathway activation reduced LAG3⁺CD4⁺ T cells.

Conclusions:

• The LEF1-LAG3 axis modulates CD4⁺ T cells during Plasmodium infection.
• LAG3⁺CD4⁺ T cells have regulatory potential, balancing immunity and immunopathology.
• Targeting LEF1-mediated repression of Lag3 could fine-tune anti-malarial immune responses.