# Coincident Antigen Processing Pathways Feed M1 and M2 MHC Class II Conformers

> **NIH NIH R21** · ALBANY MEDICAL COLLEGE · 2022 · $203,750

## Abstract

Summary:
 The current mainstream view of exogenous antigen processing postulates a pool of proteases processing
exogenous antigen within the endosome, with structurally homogeneous MHC class II (MHCII) molecules
randomly capturing resultant peptides. However, this view is an oversimplification on at least two levels. First,
work from multiple laboratories including our own has shown that MHCII molecules exist in two distinct
conformational states based on alternative pairing of transmembrane domain GxxxG dimerization motifs (i.e.,
M1 and M2 paired MHCII) and that these two MHCII conformers have distinct biological and immunological
properties. Second, we have reported that in B lymphocytes M1 and M2 paired MHCII molecules are
selectively loaded with peptide derived from different pools of exogenous antigen. M1 MHCII is loaded with
peptide derived from B cell receptor (BCR)-bound cognate antigen, whereas peptide derived from non-cognate
antigen is loaded onto both M1 and M2 MHCII. New preliminary data also reveals that ~50% of the peptides
bound to each conformer are unique to that set of molecules. As engagement of M1 and M2 peptide-MHCII
drive different levels of B and T cell activation, differential MHCII conformer peptide loading will impact the
focus, strength and quality of an immune response.
 This framework leads to the hypothesis that within an antigen presenting cells, there are two coincident
but distinct pathways of exogenous antigen processing that leads to selective peptide loading onto M1 versus
M2 paired MHCII molecules. The goal of this proposal is to define the two pathways of exogenous antigen
processing that feed the two MHCII conformers. This goal will be attained by completing two Specific Aims.
The objective of the first aim is to define/analyze the peptidomes of M1 and M2 paired MHCII isolated from
both resting and antigen-pulsed B cells. This information will point to the subcellular sites of processing for M1
vs. M2 MHCII-bound peptides by defining the pool of source antigens for each MHCII conformer. The results
will also reveal the impact of antigen targeting as well as BCR signaling-induced changes in the antigen
processing pathway on the M1 and M2 MHCII peptidomes. The objectives of the second aim are to; 1) take a
molecular genetics approach to define the structure and dynamics of the MHCII peptide loading complex (PLC)
that selectively charges peptides from BCR-bound cognate antigen onto M1 MHCII and 2) to use a discovery-
style approach to identify and characterize new PLC components.
 The potential impact of these studies is many-fold. For example, results will reveal how the form of antigen
(e.g., vaccine) provided to the immune system would impact the levels of M1 and M2 MHCII peptide loading
and thus the level of subsequent immune activation. Therapeutically, the ability to selectively interfere with M1
or M2 MHCII-restricted antigen presentation may lead to new therapeutic approaches to selectively
control/blo...

## Key facts

- **NIH application ID:** 10421469
- **Project number:** 5R21AI148730-02
- **Recipient organization:** ALBANY MEDICAL COLLEGE
- **Principal Investigator:** James R Drake
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $203,750
- **Award type:** 5
- **Project period:** 2021-06-07 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10421469

## Citation

> US National Institutes of Health, RePORTER application 10421469, Coincident Antigen Processing Pathways Feed M1 and M2 MHC Class II Conformers (5R21AI148730-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10421469. Licensed CC0.

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