# Mechanisms of T cell activation in cardiac fibrosis and non-ischemic heart failure

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2022 · $582,638

## Abstract

The goal of this new R01 application is to investigate the mechanisms of T cell activation and the
consequences in the progression of cardiac fibrosis (CF) in the deadly syndrome of heart failure (HF), currently
the leading cause of mortality and hospitalizations in the USA. We were the first to report cardiac T cell
infiltration associated with CF in patients with non-ischemic HF, and using the well- established experimental
model of HF induced by transverse aortic constriction (TAC), we and others described a major role for CD4+ T
cells as major contributors to non-ischemic HF. However, due to the complexity of the mechanisms of T cell
activation resulting in inflammation, CF and HF, no immunomodulatory or anti-fibrotic therapies have yet
translated to clinical practice to treat HF. Our preliminary data reveal the novel finding that T cell activation
occurs in the mediastinal lymph nodes that drain the heart (mLN), and also within the heart in a classic
dependent manner that involves T cell receptor (TCR) engagement by antigens presented by Major
histocompatibility complex II (MHC-II) expressed on antigen presenting cells (APC). We additionally
demonstrate that activated cardiac fibroblasts (CFB) express MHC-II and thus could function as APC in the
heart. Emerging evidence suggests that T cells can also be activated by alarmins, soluble inflammatory
mediators produced in response to sterile inflammation, through TCR independent pathways in a “non classic"
TCR- independent manner, and our in vitro and in vivo preliminary data is in support of this. Based on these
findings, we will test the central hypothesis that classic and non-classic T cell activation mechanisms cooperate
to initiate and sustain CF during the progression of HF. In aim 1, we will use Nur77GFP mice, in which T cells
express GFP only when stimulated classically through the TCR, to map the specific location and timing of
classic T cell activation during TAC. We will additionally perform single cell TCR sequencing on heart sorted
GFP+CD4+ T cells to identify the immunodominant T cell clones in HF progression. The APC responsible for
such activation and its effects in CF and HF over time will be evaluated in cell specific MHC-II-/- mice. In aim 2,
we will perform adoptive transfer experiments of WT and alarmin sensing-impaired activated CD4+ T cells into
MHC-II-/- recipient mice, which lack classic T cell activation and are normally protected from CF and HF. CF,
cardiac function and the alarmins responsible for T cell activation will be characterized in in vivo and in vitro
assays. In aim 3, based on our data indicating that activated T cell adhesion to CFB induces their
transformation to pro-fibrotic myofibroblast in a TGFβ dependent manner, we will investigate the mechanisms
of TGFβ synthesis, release and signaling in CFB in response to classically and non classically activated T cell
adhesion. We will use in vitro biochemical and molecular assays. These important studies will re...

## Key facts

- **NIH application ID:** 10334455
- **Project number:** 5R01HL144477-04
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Maria Pilar Alcaide Alonso
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $582,638
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334455

## Citation

> US National Institutes of Health, RePORTER application 10334455, Mechanisms of T cell activation in cardiac fibrosis and non-ischemic heart failure (5R01HL144477-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10334455. Licensed CC0.

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