# Chemokines and Lymphoid Tissue Organization and Function

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $562,480

## Abstract

Project Summary/Abstract
 The intestinal immune system plays crucial roles in maintaining tissue and microbiome homeostasis
and in protecting from pathogens. Two major classes of intestinal immune cells are the intraepithelial
lymphocytes (IEL) and IgA producing cells. The factors controlling the compartmentalization and homeostasis
of immune cells in different intestinal niches are incompletely understood.
 G-protein coupled receptors (GPCRs) have diverse actions in recruiting and retaining cells in tissues.
Chemoattractant receptors couple to Gαi and have critical roles in cell recruitment to the gut. Recent studies
have identified important roles for Gα13-coupled receptors in organizing lymphoid niches, but their function in
the intestinal immune system is poorly understood. In preliminary data we find that removal of Gα13 from
hematopoietic cells leads to a deficiency of γδT and αβT IEL. In Aim 1, we will define how Gα13-signaling
contributes to IEL compartmentalization and function. Lineage specific Cre lines will enable dissection of
subset selective effects and tamoxifen-inducible TCRδ-CreERT2 will be used to define the stage(s) when
Gα13 is required in the γδT IEL compartment. CD8αβ T cells will be differentiated in vitro in the presence of
retinoic acid and TGFβ to induce a gut tropic α4β7+ CCR9+ state and used in transfer experiments to dissect
the mechanism by which Gα13-deficiency impacts on CD8αβ TCRαβ IELs. The role of downstream factors
Ahrgef1, RhoA and ROCK will be investigated as well as possible cross talk with AHR. The impact of Gα13-
deficiency on the response to intestinal pathogens will be studied.
 In Aim 2, the GPCRs acting upstream of Gα13 in IEL will be characterized. Our prior work showed that
GPR18 is important for IEL competitiveness. We will test the dependence of GPR18 function on Gα13
signaling. GPR55, a lysophosphatidylinositol responsive Gα13-coupled receptor, restrains IEL interaction with
the epithelium. We will test the possibility that in the absence of Gα13, GPR55 becomes dominantly coupled to
Gαi, leading to IEL mispositioning and loss. CRISPR-based knockout in retroviral bone marrow chimeras will
be used to identify further Gα13-coupled receptors contributing to IEL homeostasis.
 During our study of conditional Gα13-deficient mice we observed an exaggerated IgA response in
mesenteric lymph nodes (MLNs) but not Peyer’s patches. Individual MLNs drain different regions of the
intestine. In Aim 3, we will examine the impact of Gα13 deficiency in each MLN type. We will identify the
stage(s) during IgA+ GC B cell generation that Gα13 acts and perform microscopy and cell contact-tracing
studies to characterize the cell-cell interactions determining the magnitude of the MLN IgA response.
 These studies will advance our understanding of cues and signaling pathways acting to promote
intestinal lymphocyte homeostasis and function. Given that GPCRs are the most drugged class of molecules,
our studies are likely to le...

## Key facts

- **NIH application ID:** 10881175
- **Project number:** 2R37AI045073-26
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jason G Cyster
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $562,480
- **Award type:** 2
- **Project period:** 1999-04-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881175

## Citation

> US National Institutes of Health, RePORTER application 10881175, Chemokines and Lymphoid Tissue Organization and Function (2R37AI045073-26). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881175. Licensed CC0.

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