An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Pro-inflammatory immune responses, while crucial for pathogen clearance, can cause severe tissue damage if unchecked.
• Excessive complement and IFN-γ responses drive immunopathogenesis and are prominent in severe SARS-CoV-2 infection.
• Mechanisms controlling the timely shutdown of these immune responses are not well understood.

Approach:

• Investigated how complement signaling influences CD4+ T helper 1 cell responses.
• Examined the role of vitamin D (VitD) and its receptor (VDR) in regulating T cell function.
• Analyzed epigenetic changes and transcription factor involvement (c-JUN, BACH2) in VitD-mediated immune suppression.
• Assessed VitD pathway function in CD4+ T cells from COVID-19 patients and psoriatic lesions.

Key Points:

• Complement induces VDR and CYP27B1 in T cells, enabling VitD activation and response.
• VitD promotes the transition from pro-inflammatory IFN-γ+ Th1 cells to IL-10+ suppressive Th1 cells.
• Epigenetic modifications, superenhancers, c-JUN, and BACH2 are crucial for this VitD-driven immune suppression.
• The VitD-mediated shutdown program is impaired in CD4+ T cells from COVID-19 patients.

Conclusions:

• Complement-triggered VitD signaling is a key mechanism for retracting pro-inflammatory Th1 responses.
• Impaired VitD pathway in COVID-19 CD4+ T cells contributes to persistent hyperinflammation.
• Adjunct therapy with VitD, potentially combined with corticosteroids like alfacalcidol, may help dampen hyperinflammation in severe COVID-19.