DUSP6 mediates T cell receptor-engaged glycolysis and restrains T_FH cell differentiation

Area of Science:

• Immunology
• Cellular Metabolism
• Molecular Signaling

Background:

• Activated T cells require metabolic reprogramming for effector function and differentiation.
• The specific factors governing T cell metabolic adaptation and follicular helper T (T_FH) cell differentiation remain incompletely understood.
• Dual-specificity phosphatase 6 (DUSP6) is implicated in regulating signaling pathways, but its role in T cell biology is unclear.

Purpose of the Study:

• To investigate the role of DUSP6 in T cell receptor (TCR) signaling.
• To determine how DUSP6 influences T_FH cell differentiation and effector function.
• To elucidate the impact of DUSP6 on T cell metabolic reprogramming.

Main Methods:

• Utilized DUSP6-deficient (DUSP6^-/-) mice and transgenic OTII-DUSP6^-/- mice.
• Performed in vitro and in vivo analyses of T_FH cell populations, IL-21 production, and antibody responses.
• Assessed T cell signaling pathways (JNK, p38), glycolysis, and mitochondrial respiration in DUSP6-deficient T cells.

Main Results:

• DUSP6 deficiency led to increased T_FH cells and elevated IL-21 production in vitro and in vivo.
• DUSP6^-/- mice exhibited enhanced antigen-specific IgG2 responses after immunization.
• Activated DUSP6^-/- T cells displayed altered signaling (increased JNK/p38 phosphorylation) and impaired glycolysis, relying on glucose-independent mitochondrial respiration.

Conclusions:

• DUSP6 acts as a negative regulator of T_FH cell differentiation and IL-21 production.
• DUSP6 connects TCR signaling to metabolic reprogramming, specifically influencing the commitment to glycolysis.
• The phosphatase DUSP6 restrains T_FH cell responses by modulating both signaling and metabolic pathways.