# CD4+ Tissue resident memory T-cells in Crohn's Disease

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $170,551

## Abstract

ABSTRACT
Crohn’s disease (CD) is a chronic condition with high morbidity and economic burden. Aberrant host
responses to dysbiotic enteric microbiota are central to the pathogenesis of CD. Consistent with this concept,
T-cell subsets closely aligned with the enteric microbiota, such as Th17 cells, are strongly implicated in CD.
Although biologics have transformed the clinical management of CD, > 50% of patients eventually fail medical
therapies and progress to surgery. Thus, characterizing pathogenic T-cell pathways is necessary to develop
new therapies and identify prognostic biomarkers in CD. Tissue-resident memory T-cells (TRM) are a recently
described subset of tissue-restricted non-circulating memory T-cells. They are antigen-specific and enriched at
sites with high microbial burden, including the intestine. These features make TRM excellent candidates to link
enteric dysbiosis with aberrant host responses. Indeed, we have reported that CD4+ TRM with a pathogenic
Th17 signature are abundant in the intestine in CD and are enriched in CD compared to non-Inflammatory
Bowel Disease (IBD) controls. Moreover, these enriched CD4+ TRM express the transcriptional repressor PR
zinc finger domain (PRDM)1. In turn, knockdown of PRDM1 with silencing RNA results in the upregulation of
the key cell trafficking molecule sphingosine 1 phosphate receptor 1 (S1PR1). As S1PR1 is by definition
suppressed in TRM, this implies that PRDM1 promotes retention of pathogenic CD4+ TRM in the intestine in CD
via transcriptional control of cell trafficking molecules. Furthermore, we find that IL-15 (which is enriched in
CD), promotes the production of inflammatory cytokines by CD4+ TRM similar to the canonical pro-inflammatory
cytokines IL-1β and IL-23. Finally, compatible with the possibility that the dysbiosis in CD drives pathogenic
CD4+ TRM, humanized gnotobiotic IL-10-/- mice with CD-microbiota develop severe colitis relative to non-IBD
control microbiota colonized counterparts. Moreover, the majority of colitogenic mucosal Th17 cells in these
mice bear TRM markers. Thus, our data indicate that the CD microbiota induced pathogenic CD4+ TRM, which
are regulated by PRDM1 and IL-15. Herein, we propose to 1) determine the mechanism and predictive
capacity of PRDM1 in CD, 2) delineate the role of IL-15 in CD4+ TRM and 3) using humanized gnotobiotic mice
colonized with microbiota from CD patients and healthy controls, define the extent to which CD microbiota
induces pathogenic CD4+ TRM.

## Key facts

- **NIH application ID:** 10054822
- **Project number:** 1K08DK123403-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Shrinivas Bishu
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $170,551
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054822

## Citation

> US National Institutes of Health, RePORTER application 10054822, CD4+ Tissue resident memory T-cells in Crohn's Disease (1K08DK123403-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10054822. Licensed CC0.

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