Structural insights into human MHC-II association with invariant chain

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• Major histocompatibility complex II (MHC-II) presents peptides to T cells, a crucial step in adaptive immunity.
• The invariant chain (Ii) guides MHC-II biosynthesis, preventing premature peptide loading and facilitating processing into MHC-II-CLIP.

Purpose of the Study:

• To elucidate the structural basis of Human Leukocyte Antigen (HLA)-DR and HLA-DQ complex assembly with the invariant chain (Ii).
• To define atomic-level interactions within the HLA/Ii complex and its components.

Main Methods:

• Cryo-electron microscopy was used to resolve structures of full-length HLA-DR and HLA-DQ complexes associated with Ii.
• Structures were resolved at 3.0 to 3.1 Å resolution.

Main Results:

• The trimeric assembly of the HLA/Ii complex was elucidated.
• Atomic-level interactions between HLA, Ii transmembrane domains, loop domains, and class II-associated invariant chain peptides (CLIP) were defined.
• These findings complement existing structures of MHC-II peptide loading intermediates (DO and DM).

Conclusions:

• The study provides a complete structural pathway for class II antigen presentation.
• Understanding these molecular interactions is key to comprehending adaptive immunity and developing related therapeutics.