IL-17-dependent fibroblastic reticular cell training boosts tissue protective mucosal immunity through...

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• Innate immune training, enhanced by vaccination, improves responses to new infections.
• Fibroblastic reticular cells (FRCs) are crucial stromal cells in lymphoid organs, supporting lymphocytes and modulating adaptive immunity.
• IL-17 signaling influences FRC metabolism and proliferation during inflammation.

Purpose of the Study:

• To investigate if prior inflammatory activation of FRCs alters immune responses to the gut pathogen Citrobacter rodentium.
• To determine the role of FRC-intrinsic IL-17 signaling in protective immunity against C. rodentium.

Main Methods:

• Induction of nonspecific gut inflammatory training in a mouse model.
• Analysis of FRC activation, proliferation, and metabolic responses in mesenteric lymph nodes (MLNs).
• Assessment of antibody production, bacterial clearance, and colon inflammation following C. rodentium infection.
• Investigation of IL-17 and IL-10 signaling pathways.

Main Results:

• Inflammatory training increased activated FRCs in MLNs and enhanced IL-17-dependent antibody responses to C. rodentium.
• FRCs exhibited hallmarks of innate immune training, including epigenetic and metabolic changes, persisting for at least 6 weeks.
• While bacterial infection kinetics remained unchanged, colon inflammation was paradoxically reduced.
• IL-10 production by activated B cells was essential for the protective effects of inflammatory training on the colon.

Conclusions:

• FRC-intrinsic IL-17 signaling is critical for protective antibody immunity against C. rodentium.
• Nonspecific gut inflammatory training can induce lasting innate immune training in FRCs.
• This immune training enhances protective antibody and IL-10 responses, leading to infection clearance with reduced tissue damage, highlighting a novel mechanism for preserving host health.