# Role of Cul4A in Governing Th2-Type Tolerance

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $400,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The hallmark of allergic diseases is the infiltration/accumulation of Th2 cells at the sites of inflammation;
however the mechanisms governing the development of unwanted Th2-driven airway diseases are poorly
understood. Thus, today it is becoming clear that understanding the Th2-type immune responses and ways
to control them may prove to be invaluable for the treatment of allergic inflammation.
 Recently, we as well as others, have demonstrated the role of E3 ubiquitin ligases in T cell tolerance.
Cullin4A (Cul4A) belongs to the evolutionally conserved E3 ligase family and has been suggested to be
involved in hematopoietic cell activation and in chromatin regulation; however, the role of Cul4A in T
lymphocytes has not been addressed yet. Interestingly, expression of Cul4A was upregulated in tolerant T
cells. Moreover, Cul4A knockout (KO) CD4+ T cells activated in vitro and in vivo under tolerogenic conditions
exhibited an enhanced level of proliferation along with IL-2 and IL-4 production compared to wild-type cells,
suggesting an important role of Cul4A in regulation of T cell tolerance. Strikingly, we found that Cul4A KO
effector T cells and Treg cells expressed higher levels of Th2 but not Th1 and Th17 cytokines, which correlates
with increased levels of IgG1 and IgE in the sera of Cul4A KO mice, indicating the selective role of Cul4A in
controlling inflammatory Th2-type responses. Importantly, we detected reduced Cul4A expression in CD4+ T
cells from asthmatic patients compared to CD4+ T cells from healthy donors, further indicating that Cul4A
potentially contributes to airway immune tolerance induction. In addition, shRNA knockdown of Cul4A in
human CD4+ T cells resulted in upregulated expression of Th2-specific cytokines. Based on these findings, we
hypothesize that regulation of Th2-type immune responses by Cul4A may be an important checkpoint
in airway tolerance induction, which is crucial to prevent development of allergic diseases.
 In Aim 1, we propose to determine the mechanisms whereby Cul4A controls T cell activation by utilizing
gene knockdown approaches and in vitro and in vivo Th2 tolerance induction models. In Aim 2, we will
determine the role of Cul4A in Th2 cell programming and its underlying mechanisms as well. We will employ
cutting edge technologies, including two-hybrid screening and microarray analysis of gene expression, to
identify the exact target(s) of Cul4A to determine its function in Th2 development. In addition, we will assess
the cellular mechanisms whereby Cul4A controls Th2 type-driven allergic asthma. In Aim 3, we will determine
the mechanism by which Cul4A regulates Treg function, particularly in controlling Th2 inflammatory
responses. The physiological significance of this finding will be analyzed in different in vivo models.
 The proposed research will provide new significant insight into characterization of mechanisms
underlying Cul4A-mediated Th2-type tolerance that may potential...

## Key facts

- **NIH application ID:** 9939689
- **Project number:** 5R01HL143520-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Roza Insafetdinovna Nurieva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939689

## Citation

> US National Institutes of Health, RePORTER application 9939689, Role of Cul4A in Governing Th2-Type Tolerance (5R01HL143520-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939689. Licensed CC0.

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