# Recognition of Mtb-Infected Cells by Non-Classically Restricted CD8+ T Cells

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2021 · —

## Abstract

Project Summary
Tuberculosis (TB) is a leading cause of infectious disease mortality worldwide, accounting for 10.4 million new
cases and 1.3 million deaths annually. An understanding of the immune response to Mtb is of central importance
in the development of improved vaccines. In this regard our laboratory, under the auspices of the VA Merit
Program, has defined Mucosal Associated Invariant T (MAIT) cells as a class of cells that are restricted by the
highly conserved MR1 molecule, recognize Mtb-infected cells, have effector capacity in the thymus and cord
blood, yet display evidence for memory following exposure to Mtb, and are enriched in the lungs.
MAIT cells are found in tissues such as the lung and intestine. Because MAIT cells recognize small molecules,
such as metabolites of riboflavin, we postulate that the cell surface expression of MR1 is tightly regulated to
avoid activation of these cells in the absence of intracellular infection. Indeed, with the support of the VA Merit
Program, we have found that MR1 is both located in an endosome, requires a ligand for translocation to the cell
surface, and is dependent on vesicular trafficking for the presentation of Mtb-derived antigens to MR1T cells.
Furthermore, we find that the mechanisms underlying presentation of Mtb-derived antigens can be distinguished
from antigens that are exogenously delivered, suggesting that there are specialized mechanisms for sampling
the intracellular environment.
Therefore, in this application we will focus on defining the molecular mechanisms that allow for the appropriate
presentation of intracellular infection, with a focus on Mtb. We will 1) Define the molecular chaperones required
for the presentation of microbials ligands, and 2) Define the role of MR1 SNPs and splice variants in controlling
the recognition of the Mtb infected cell, and will evaluate these variants in clinically relevant outcomes following
exposure to Mtb.
This project contains two Aims:
AIM 1: Define the molecular chaperones necessary for the presentation of Mtb-derived ligands
1a. Determine the molecular chaperones associated with MR1.
1b. Determine the role of riboflavin transporters in the uptake or trafficking of MR1 ligands.
AIM 2: Define the role of MR1 SNPs and splice variants in human susceptibility to TB
2a. Determine the relationship of MR1 SNPs and splice variants and clinical outcomes associated with
 exposure to Mtb.
2b. Determine the functional significance of MR1 SNPs.
2c. Determine the relationship of MR1 splice variant expression and the capacity of cells to present MR1
 ligands to MR1T cells.

## Key facts

- **NIH application ID:** 10124862
- **Project number:** 2I01BX000533-09A1
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** DAVID M. LEWINSOHN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2010-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124862

## Citation

> US National Institutes of Health, RePORTER application 10124862, Recognition of Mtb-Infected Cells by Non-Classically Restricted CD8+ T Cells (2I01BX000533-09A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10124862. Licensed CC0.

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