# A new mouse model to study the function of CD1b-restricted germline encoded, mycolyl lipid-reactive (GEM) T cells

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2024 · $200,000

## Abstract

PROJECT SUMMARY
Group 1 CD1-restricted T cells are a subset of the unconventional T cells that recognize lipid and glycolipid
antigens presented by CD1a, CD1b, and CD1c molecules. The role of group 1 CD1-restricted T cells has been
best established in Mycobacterium tuberculosis (Mtb) infection in which a wide variety of lipid antigens have
been identified. Analysis of the T cell response during human Mtb infection indicated that infected individuals
have increased CD1-restricted T cell responses to lipid antigens compared to Mtb na"ive controls. CD1 brestricted
T cells present in bronchioalveolar fluid were shown to limit Mtb growth ex vivo and the frequency of
these polycycotoxic Mtb lipid-reactive T cells correlated with protection from active tuberculosis disease.
Furthermore, we have previously shown that Mtb lipid-specific group 1 CD1-restricted T cells were able to
expand during Mtb infection in humanized CD1 transgenic (hCD1Tg) mice. Adoptive transfer of transgenic T
cells specific to mycolic acid presented by CD1 b led to decreased bacterial burden in Mtb-infected Ragdeficient
mice in a group 1 CD1-dependent manner. Taken together, these studies show that Mtb lipid-specific
group 1 CD1-restricted T cells are an important component of the cellular immune response to Mtb.
While most of group 1 CD1-restricted T cells express diverse αβ TCRs, most humans harbor a population
of CD1b-restricted T cells known as "germline encoded mycolyl-reactive" (GEM) T cells that express an
invariant TRAV1-2-TRAJ9 TCR-α chain. GEM T cells show high affinity binding to CD1b/glucose
monomycolate (GMM) and secrete IFN-γ and TNF-α in response to GMM stimulation. To investigate the in
vivo function of this conserved CD1b/GMM-specific T cell subset during Mtb infection, we generated a hCD1Tg
background TCR transgenic mice encoding GEM TCR specific for CD1b/GMM. In Aim 1, we propose to
determine if the expression of CD4 or CD8 co-receptor affects the antigen response of GEM T cells. In
addition, we will assess the ability of GEM T cells to traffic to the lung and confer protection against Mtb
infection. The effector functions important for GEM T cell-mediated anti-mycobacterial immunity will also be
evaluated. In Aim 2, we propose to address whether GEM T cells have the capacity to generate memory T cell
responses. We will use a novel vaccination and re-challenge model that allows for complete clearance of an
attenuated Mtb strain prior to challenge with fully virulent Mtb to study memory GEM T cell responses. Using
this approach, we will compare the activation kinetics, tissue localization, and effector functions of GEM T cells
during primary and secondary response to Mtb infection. We will also analyze gene expression profiles of
memory GEM T cells and compare to that of conventional memory T cells. Collectively, these studies will yield
a better understanding of how group 1 CD1-restricted T cells contribute to the overall immune response
against Mtb and whether t...

## Key facts

- **NIH application ID:** 10867411
- **Project number:** 5R21AI178629-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Chyung-Ru Wang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $200,000
- **Award type:** 5
- **Project period:** 2023-06-14 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867411

## Citation

> US National Institutes of Health, RePORTER application 10867411, A new mouse model to study the function of CD1b-restricted germline encoded, mycolyl lipid-reactive (GEM) T cells (5R21AI178629-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10867411. Licensed CC0.

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