RORγt phosphorylation protects against T cell-mediated inflammation.

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• RAR-related orphan receptor-γ (RORγt) is a key transcription factor in immune cell differentiation and lymphoid tissue development.
• Serine 182 phosphorylation is a major post-translational modification of RORγt, but its in vivo function remains largely unknown.
• Understanding RORγt post-translational modifications is critical for deciphering immune regulation and autoimmune disease pathogenesis.

Purpose of the Study:

• To investigate the in vivo role of serine 182 phosphorylation (S182 PTM) on RORγt in T cell development and immune responses.
• To elucidate the signaling pathways regulating RORγt S182 phosphorylation and its functional consequences.
• To determine the contribution of RORγt S182 PTM to the pathogenesis of T cell-mediated inflammatory diseases.

Main Methods:

• Generation and analysis of RORγt S182A knockin mice.
• Assessment of thymic T cell development and peripheral effector T cell differentiation.
• Evaluation of inflammatory responses in mouse models of colitis and experimental autoimmune encephalomyelitis (EAE).
• Investigation of the upstream signaling pathways, including IL-1β and ERK, involved in RORγt S182 phosphorylation.

Main Results:

• RORγt S182 phosphorylation is dispensable for thymic T cell development and effector T cell differentiation.
• This PTM is a critical regulator of inflammation, downstream of IL-1β and ERK signaling.
• ERK-mediated phosphorylation of RORγt at S182 restrains Th17 cell hyperactivation and enhances IL-10 production in RORγt+ Treg cells.
• Phospho-null RORγt S182A mice exhibit exacerbated inflammation in colitis and EAE models.

Conclusions:

• The IL-1β-ERK-RORγt S182 phosphorylation axis acts as a crucial negative feedback mechanism controlling T cell-mediated inflammation.
• RORγt S182 phosphorylation plays a protective role against autoimmune diseases by balancing pro- and anti-inflammatory responses.
• Targeting the IL-1β-ERK-RORγt S182 pathway offers potential therapeutic strategies for autoimmune disorders.