Unraveling the Supramolecular Architecture of Molecular Machineries in Adaptive Immunity

Introduction

To combat daily threats of pathogens and abnormal cells, the human organism features a sophisticated defense mechanism called the adaptive immune system. In broad terms, this intricate mechanism is triggered by specific peptide epitopes presented on molecules of the major histocompatibility complex class I (MHC I), which are scanned by cytotoxic T cells.

Mechanisms Involved

Intracellular transport, loading, and cell-surface recognition of antigenic peptides on MHC I are orchestrated by machineries, including:

• The peptide-loading complex (PLC)
• The T cell receptor (TCR) complex

The PLC is composed of multiple subunits, including the antigen translocation unit TAP, the MHC I heterodimer, and several chaperones ensuring that only stable peptide-MHC I molecules are released to the cell surface for decoding by TCR complexes.

Signaling and Hypothesis

Ligand binding and the supramolecular organization of TCR complexes are translated into phosphorylation of conserved tyrosine-containing cytosolic sequence motifs that initiate downstream signaling cascades. Based on their incredible efficiency and selectivity, we hypothesize that:

1. The biogenesis of MHC I is highly processive and coupled via allosteric networking.
2. Antigen processing and recognition machineries are compartmentalized by a defined supramolecular organization.

Challenges in Understanding

However, despite their fundamental importance, these architectural details of the PLC and the TCR, as well as the dynamic networking included in the quality control of the endoplasmic reticulum (ER) and receptor signaling processes, remain enigmatic due to their inherent dynamics, low abundance, and complexity.

Project Goals

This ambitious proposal will contribute to a long-awaited holistic understanding of the machineries that shape the vertebrate adaptive immunity. The expected findings from this project will be groundbreaking in understanding the hidden processes of epitope selection and reception in human disease.