# MicroRNA-mediated control of immune responses and tolerance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $394,479

## Abstract

Like transcription factors, microRNAs (miRNAs), a class of short regulatory non-coding RNAs known for their
role in organ development, cellular differentiation, homeostasis, and function, have been extensively studied
for their roles in controlling expression of different sets of genes that dictates the outcome of developmental
transitions or cellular activation status of the immune cell populations. Previously, we have identified an
important miRNA family, miR-23~27~24 clusters that play a diverse role in regulating the differentiation and
function of multiple CD4+ helper T (Th) cell lineages as well as regulatory T (Treg) cells. Our work has shown
that proper gene regulation by the miR-23~27~24 in CD4+ T cells is crucial to ensure the optimal balance
between immunity and tolerance. Loss of miR-23~27~24 clusters in T cells resulted in dysregulated follicular
helper (Tfh) cell responses when mice aged and severe Th2-driven airway inflammation upon challenges of
different allergens. On the other hand, excessive expression of members of this miRNA family would also
lead to the development of autoimmunity through both promoting the proinflammatory cytokine production by
effector T (Teff) cells as well as impairing Treg cell homeostasis and function. Considering that many of the
miRNA family targets identified in our previous work are also known to function in other immune cell
populations, miR-23~27~24 clusters likely have a broader impact on the immune system beyond their role in
regulating CD4+ T cell immunity. Here, we propose a multifaceted study employing genetic, biochemical,
immunological approaches and whole animal experimentation to comprehensively examine the molecular
and cellular mechanisms underlying miR-23 cluster-mediated immune regulation. In particular, while we will
expand our efforts in studying this miRNA family in T cell immunity with a new focus on CD8+ T cell-mediated
immune responses, we will also examine their potential new roles in both Tfh cells and B cells that are crucial
for establishment of germinal center (GC) reactions and the resultant humoral immunity. Next, by combining
RNA-seq, ChIP-seq approaches with newly developed IR-CLASH technology, we will explore the putative
molecular mechanisms underlying miR-23 cluster-dependent immune regulation through identification of
genes that are regulated in miR-23 cluster-dependent manner and through identification of targets that are
directly controlled by miR-23 cluster. Collective, the over-arching goal of the current proposal is to not only
establish a powerful model to dissect the molecular orchestration of cellular differentiation, function, and
homeostasis in the adaptive immune system but also build a solid foundation with which to target the
miR-23~27~24 family to combat infections and a wide array of human immunological diseases.

## Key facts

- **NIH application ID:** 10098286
- **Project number:** 5R01AI108651-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Li-Fan Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,479
- **Award type:** 5
- **Project period:** 2014-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098286

## Citation

> US National Institutes of Health, RePORTER application 10098286, MicroRNA-mediated control of immune responses and tolerance (5R01AI108651-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10098286. Licensed CC0.

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