Immune Cell Derived 1,25(OH)2D3: A Critical Defense Against Influenza Infection

Introduction/Rationale: Immune cells have vitamin D receptors (VDR) making them direct targets of vitamin D. CYP27B1 is the critical enzyme that hydroxylates circulating, inactive 25(OH)D to form the active, high affinity VDR binding, 1,25(OH)2D. CYP27B1 is expressed primarily in the kidney; however, immune cells can also express CYP27B1. Activated macrophages and T cells have been shown to produce 1,25(OH)2D. The role of immune cell derived 1,25(OH)2D in host resistance to influenza infection was examined here.

Methods: To investigate the role of CYP27B1 in host resistance to respiratory infection, whole body CYP27B1 knockout (KO) mice and mice with a deletion in the ability of the kidney to make 1,25(OH)2D (double intronic CYP27B1 renal deletion, DIKO) were infected with mouse adapted H1N1 influenza A. DIKO mice only express extra renal CYP27B1 that includes immune cell produced 1,25(OH)2D.

Results: Influenza infected CYP27B1 KO mice developed severe respiratory symptoms and significantly more lethality compared to wildtype (WT) littermates. Influenza infection of DIKO mice was not different than in WT mice, indicating that immune cell production of 1,25(OH)2D is protective during influenza. CD8+ T cells from CYP27B1 KO mice had impaired granzyme B responses and lack of PD-1 activation as compared to WT littermates. This data supports a role for immune cell production of 1,25(OH)2D which is critical for the cytotoxic function of CD8+ T cells. Experiments are underway to determine the effect of T cell specific CYP27B1 deletion in response to influenza infection.

Conclusion: Immune cell derived 1,25(OH)2D is a critical regulator of influenza pathogenesis and is required for granzyme B production by CD8+ T cells. Understanding the mechanisms that regulate local 1,25(OH)2D production in T cells or other immune cell types is needed for future recommendations that might include vitamin D supplementation for the prevention or treatment of viral respiratory infections.