Counter-regulation of T cell effector function by differentially activated p38

Area of Science:

• Immunology
• Cell Signaling
• Molecular Biology

Background:

• The p38 kinase pathway is activated through various stress-induced and receptor-mediated signaling cascades.
• T cell receptor (TCR) signaling activates p38 via an alternative pathway involving phosphorylation at Tyr-323 (pY323), distinct from the canonical MAP kinase (MAPK) cascade.

Purpose of the Study:

• To investigate the differential roles of p38 activation pathways in T cell function.
• To elucidate the downstream targets and immunological consequences of alternative p38 activation via TCR signaling.
• To explore the therapeutic implications of these findings in the context of psoriasis and phototherapy.

Main Methods:

• Utilized genetically modified mice expressing p38α and p38β with Y323F substitutions to block alternative pathway activation.
• Analyzed the phosphorylation status of p38 and its downstream targets, NFATc1 and IRF4, in response to TCR stimulation and external stimuli (UV, osmotic shock).
• Assessed T cell proliferation, cytokine production (IL-17), and transcription factor expression in both mouse models and human psoriatic lesions.

Main Results:

• Alternative p38 activation (pY323) up-regulates transcription factors NFATc1 and IRF4, promoting T cell proliferation and cytokine production.
• MAPK cascade activation of p38, or p38 activation by UV/osmotic shock, inhibits TCR-mediated NFATc1 activation and promotes its cytoplasmic retention.
• UVB treatment of human psoriatic lesions decreased pY323(+) T cells, reducing IRF4 and IL-17 levels in the skin.

Conclusions:

• Distinct p38 activation mechanisms converge on NFATc1, exerting opposing effects on T cell immunity.
• Alternative p38 activation is crucial for TCR-induced T cell responses, while stress-induced activation can suppress them.
• The differential regulation of p38 by TCR signaling and external stimuli may explain the therapeutic efficacy of phototherapy in psoriasis.