TAP dysfunction in dendritic cells enables noncanonical cross-presentation for T cell priming

Area of Science:

• Immunology
• Cellular Biology
• Virology

Background:

• Major histocompatibility complex class I (MHC-I) presentation is crucial for adaptive immunity.
• Viruses often evade immune detection by inhibiting the transporter associated with antigen processing (TAP).
• CD8+ T cell priming typically relies on TAP-dependent MHC-I presentation or cross-presentation by dendritic cells.

Purpose of the Study:

• To investigate mechanisms of CD8+ T cell priming during viral infections when TAP function is compromised.
• To identify alternative pathways for antigen presentation in the absence of canonical MHC-I presentation.
• To understand how the immune system overcomes viral evasion strategies targeting antigen presentation.

Main Methods:

• Utilized a model of viral infection with TAP blockade in hematopoietic cells.
• Analyzed the localization and trafficking of MHC-I molecules within dendritic cells.
• Investigated the role of the ER-Golgi intermediate compartment (ERGIC) and Sec22b in antigen presentation.
• Assessed CD8+ T cell mobilization and protective immunity.

Main Results:

• TAP blockade impairs MHC-I presentation and Toll-like receptor-regulated cross-presentation by depleting endosomal recycling compartments.
• MHC-I molecules accumulate in the ERGIC when TAP is blocked.
• ERGIC-derived MHC-I, via Sec22b, mediates a noncanonical cross-presentation pathway.
• This alternative pathway rescues CD8+ T cell priming despite TAP dysfunction.

Conclusions:

• A cell-autonomous, noncanonical cross-presentation pathway exists that bypasses TAP dependency.
• This ERGIC-mediated pathway compensates for impaired classical MHC-I presentation and endosomal cross-presentation.
• This mechanism is critical for mounting protective CD8+ T cell responses against viruses that inhibit TAP.