GITR controls intestinal inflammation by suppressing IL-15-dependent NK cell activity

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Glucocorticoid-induced TNFR family related gene (GITR) is a TNFR superfamily member on immune cells.
• GITR's role in T cell immunity is known, but its function in innate intestinal immunity is unclear.

Purpose of the Study:

• To investigate the role of GITR in innate immune responses within intestinal tissues.
• To elucidate GITR's impact on natural killer (NK) cell function during intestinal inflammation.

Main Methods:

• Utilized a dextran sulfate sodium (DSS)-induced colitis mouse model.
• Compared inflammation severity and immune cell infiltration in wild-type, GITR-deficient (Gitr-/-), and T cell-deficient (Rag2-/- Gitr-/-) mice.
• Administered anti-GITR agonistic antibody to assess therapeutic effects.

Main Results:

• GITR-deficient mice exhibited increased susceptibility to acute intestinal inflammation.
• Accumulation of activated NK cells was significantly higher in the colonic lamina propria of Gitr-/- mice.
• Engaging GITR with an antibody suppressed IL-15-mediated NK cell activation, proliferation, and cytokine/cytotoxic granule production, alleviating colitis in T cell-deficient mice.

Conclusions:

• GITR plays a crucial negative regulatory role in intestinal inflammation.
• GITR exerts its anti-inflammatory effects by modulating NK cell functions, including activation and proliferation.
• This study provides the first evidence of GITR's inhibitory control over innate immunity in the gut.