Related Experiment Video
Updated: Sep 17, 2025
07:37
An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
Published on: June 6, 2025
371
STAT3 phosphorylation in the rheumatoid arthritis immunological synapse
Hila Novak-Kotzer1, Jesusa Capera2, Ashwin Jainarayanan2
1Skirball Institute of Biomolecular Medicine, NYU Langone Medical Center, New York, NY, 10016, USA; Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, OX3 7FY, UK.
Journal of Autoimmunity
|July 3, 2025
Summary
A new JAK-independent pathway activating STAT3 in T cells via the immunological synapse is discovered. This pathway, involving LCK and TCR, is impaired in Rheumatoid Arthritis (RA), offering novel therapeutic targets for refractory patients.
Area of Science:
- Immunology
- Rheumatology
- Cellular Signaling
Background:
- Targeting the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway is a primary strategy for Rheumatoid Arthritis (RA).
- JAK inhibitors are effective but a subset of RA patients do not respond to this therapy, necessitating alternative treatments.
Purpose of the Study:
- To identify novel mechanisms of STAT3 activation independent of JAK signaling in T cells.
- To investigate the role of the immunological synapse (IS) in T cell activation and its potential relevance to RA pathogenesis.
Main Methods:
- Analysis of STAT3 activation in naive CD4+ T cells during immunological synapse formation.
- Investigating the role of LCK (lymphocyte-specific protein tyrosine kinase) and TCR (T-cell receptor) in STAT3 phosphorylation at the IS.
- Comparing the synaptic LCK/TCR-STAT3 pathway in healthy individuals versus RA patients.
Main Results:
- A novel JAK-independent pathway for STAT3 activation was identified, triggered by IS formation in naive CD4+ T cells.
- LCK was shown to mediate TCR-dependent STAT3 phosphorylation at the IS, representing a key event in early T cell activation.
- The synaptic LCK/TCR-STAT3 pathway was found to be impaired in patients with Rheumatoid Arthritis.
Conclusions:
- The LCK/TCR-STAT3 pathway at the immunological synapse is a previously unrecognized mechanism of T cell activation.
- This pathway represents a potential therapeutic target for Rheumatoid Arthritis, particularly for patients resistant to JAK inhibitors.
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