Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses

Area of Science:

• Immunology
• Transplantation Immunology
• Inflammation Research

Background:

• Interleukin-17 (IL-17)-dependent autoimmunity to collagen type V (Col V) is linked to obliterative bronchiolitis after lung transplantation.
• Th17 responses to Col V and Th1/17 responses in coronary artery disease require IL-1β, TNF-α, and CD14(+) cells.
• The P2X7 receptor (P2X7R) is involved in monocyte IL-1β responses, suggesting a potential role in Th17-mediated inflammation.

Purpose of the Study:

• To investigate the role of P2X7R in Th17-, Th1/17-, and Th1-mediated proinflammatory responses.
• To determine if P2X7R antagonists can selectively inhibit Col V-specific autoimmunity.
• To explore the therapeutic potential of P2X7R inhibitors in transplant-related pathologies.

Main Methods:

• Transfer of antigen-pulsed peripheral blood mononuclear cells (PBMCs) from Col V-reactive patients into SCID mouse footpads with P2X7R antagonists.
• Assessment of IL-1β induction from monocytes in response to Col V peptides and native Col V.
• Analysis of P2X7R expression on CD4+ T cell subsets (Th17 vs. Th1) in PBMCs.
• Evaluation of P2X7R inhibitor effects on alloimmunity in a heart transplant patient.

Main Results:

• P2X7R antagonists selectively inhibited Col V-specific swelling responses in mice, but not Tetanus Toxoid (TT)-specific responses.
• P2X7R inhibitors blocked IL-1β induction from monocytes for both T-dependent and T-independent Col V responses.
• Higher P2X7R expression was observed on Th17 cells compared to Th1 cells.
• P2X7R inhibitors suppressed anti-Col V autoimmunity and Th1/17-mediated alloimmunity without affecting anti-viral responses.

Conclusions:

• P2X7R plays a critical role in Th17- and Th1/17-mediated inflammatory responses, including autoimmunity and alloimmunity.
• Targeting P2X7R offers a potential strategy for treating Th17-related transplant pathologies.
• P2X7R inhibition may preserve essential Th1-mediated immunity against infections during transplantation treatment.