# KLF10, CD4+ T cells, and transplant arteriopathy

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $420,500

## Abstract

Transplant-associated arteriopathy (TAA) constitutes the major cause of graft failure and death in recipients
who survive more than one year after cardiac transplantation, despite advances in immunosuppression. One of
the early events leading to TAA is infiltration and activation of peri-adventitial inflammatory cells, including T
cells and macrophages, which is followed by the formation of a diffuse, concentric neointima in which smooth
muscle cells and leukocytes accumulate. Both T cell effectors and T regulatory cells play key roles in
regulating the balance of allograft inflammation. Interestingly, age-related diminution of T cell responsiveness
to mitogen signals have been linked to improved allograft survival. Indeed, epidemiological studies indicate that
older recipients have reduced allograft rejection rates than younger recipients. As such, identification of factors
that reduce activation of T cells could potentially impact both acute and chronic cardiac allograft rejection.
Kruppel-like factors are transcriptional regulators of cell growth, differentiation, and activation. We identified a
member of this family, KLF10, whose expression is highly expressed in T cells and increases with age. We
identified that the TGF-b1-responsive factor, KLF10, regulates key aspects of both T cell effector and T
regulatory cell function. Our preliminary studies uncover a novel role for KLF10 in age-related diminution of T
cell activation in TAA. Major histocompatibility complex class II (MHC II)-mismatched cardiac allografts showed
similar TAA and survival when transplanted into young recipients of either wild-type (WT) or KLF10-/- mice. In
contrast, allografts in older KLF10-/- recipients developed accelerated TAA with increased accumulation of peri-
adventitial T cells and macrophages, increased levels of pro-inflammatory markers (e.g. IFN-γ, TNF-a, IL-6,
and MCP-1), and reduced survival. Older KLF10-/- CD4+ T cells exhibited enhanced Th1 and decreased T
regulatory cell (Treg) function with reduced expression of CTLA-4, an immunosuppressive molecule implicated
in T cell responsiveness with aging. Finally, cardiac allografts transplanted into younger KLF10-/- hosts
receiving older KLF10-/- T cells (vs. younger KLF10-/- T cells) showed increased TAA. Mechanistic studies
demonstrate that KLF10 is targeted by a microRNA, miR-340, that is inversely expressed with KLF10 with
increasing age to regulate TGF-b1/CTLA-4 signaling. These observations provide the foundation for our central
hypothesis that KLF10 serves as a critical regulator of T cell responsiveness with aging and TAA. In Aim1, we
will explore the upstream mechanisms regulating KLF10 expression in old and young T cell effectors. In Aim2,
we will determine the molecular basis for impaired Th1 and Treg cell function in older CD4-KLF10-deficient
mice critical for TAA. In Aim3, we will explore the effect of altered KLF10 expression on T cell responsiveness
and experimental TAA using young and old, T ce...

## Key facts

- **NIH application ID:** 9838287
- **Project number:** 5R01HL134849-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MARK W FEINBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,500
- **Award type:** 5
- **Project period:** 2016-12-15 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838287

## Citation

> US National Institutes of Health, RePORTER application 9838287, KLF10, CD4+ T cells, and transplant arteriopathy (5R01HL134849-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838287. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*