Peptidases released by necrotic cells control CD8+ T cell cross-priming

Area of Science:

• Immunology
• Cancer Research
• Cell Biology

Background:

• CD8+ T cell priming is crucial for anti-tumor immunity and cancer therapies.
• The immunogenicity of necrotic cell death remains controversial, impacting antigen presentation.
• Understanding signals from dead cells is key to modulating adaptive immune responses.

Purpose of the Study:

• To investigate the role of sterile necrotic cells in CD8+ T cell priming.
• To uncover molecular mechanisms regulating T cell responses during necrosis.
• To determine if necrotic cell immunogenicity can be manipulated for therapeutic benefit.

Main Methods:

• Utilized a mouse model of sterile necrosis, injecting sterile primary necrotic cells.
• Investigated the function of cellular peptidases dipeptidyl peptidase 3 (DPP-3) and thimet oligopeptidase 1 (TOP-1).
• Assessed CD8+ T cell responses and antigen cross-presentation in vitro and in vivo.

Main Results:

• DPP-3 and TOP-1 in necrotic cells degrade proteasomal products, inhibiting antigen cross-presentation.
• Sterile necrotic tumor cells, expressing active DPP-3 and TOP-1, failed to induce CD8+ T cell responses.
• Inactivating DPP-3 and TOP-1 reversed the nonimmunogenicity of necrotic cells, restoring T cell responses.

Conclusions:

• The immunogenicity of sterile necrosis is regulated by proteasome-dependent oligopeptide generation.
• The functional status of peptidases like DPP-3 and TOP-1 in antigen donor cells controls T cell cross-priming.
• Targeting these peptidases offers a strategy to enhance anti-tumor immunity via necrotic cell vaccination.