Regulation of T cell immune response in Heart Failure with Preserved Ejection Fraction

The goal of this R01 application is to investigate the mechanisms by which T cells contribute to heart failure
(HF) with preserved ejection fraction (HFpEF), affecting roughly 50% of the HF patients. Notably, the
treatments that improve survival and outcomes in patients with HF with reduced ejection fraction (HFrEF)
have not provided clinical benefit in HFpEF patients, who often present with multiple comorbidities that
include obesity and hypertension. Correlative epidemiological studies in HFpEF patients, suggest a potential
contribution of inflammation to HFpEF. However the underlying immune mechanisms remain largely
unexplored. A unique myocardial hallmark of human HFpEF replicated in a pre-clinical model of
cardiometabolic HFpEF is the downregulation of the unfolded protein response (UPR), which results in the
cellular inability to cope with endoplasmic reticulum (ER) stress, the central function of the UPR, thus
impairing cardiomyocyte relaxation. Our preliminary data using an experimental model of cardiometabolic
HFpEF reveal the novel finding that cardiac T cell infiltration co-exists with diastolic dysfunction and
cardiomyocyte hypertrophy, and that T cell deficient mice (Tcra-/-) do not develop diastolic dysfunction or
cardiomyocyte hypertrophy under the same conditions. Our data also reveal that genes encoding specific
ER stress response factors such as X-box protein 1 (XBP1s) and activating transcription factor 6 (ATF6), are
remarkably downregulated in CD4+ T cells isolated from mice with cardiometabolic HFpEF, and not in T cells
from mice with HFrEF. T cell downregulation of XBP1s has been implicated in enhanced T cell effector
function and anti-tumor activity. This proposal will test the central hypothesis that dysregulation of T cell-
intrinsic ER stress responses promotes detrimental inflammation in cardiometabolic HFpEF. In Aim1, we will
use single cell antibody and RNA sequencing (CITE-Seq) to uncover the T cell transcriptional profiles
throughout the development of cardiometabolic HFpEF in WT mice, investigate the antigen dependence of
the T cell response, the dominant T cell subsets involved, and their ability to rescue the protective phenotype
observed in Tcra-/- recipient mice. In Aim 2, we will determine the expression of the T cell UPR during the
progression of cardiometabolic HFpEF and utilize gain-and loss-of- function approaches to define the
mechanisms by which the T cell UPR is compromised in cardiometabolic HFpEF and impacts T cell pro-
inflammatory effector function. In Aim 3, we will investigate the functional role of the T cell-intrinsic ER stress
response in cardiomyocyte hypertrophy and function during the progression of HFpEF and the T cell derived
factors altered by the compromised UPR that impact cardiomyocyte hypertrophy and function, using mice
selectively lacking UPR effectors in T cells, and gain of function approaches,.
Successful accomplishment of the Aims proposed is expected to identify novel T cell intrinsic mechanisms
that foster detrimental immune responses in HFpEF, paving the way for the development of new
immunomodulatory strategies to confront this deadly syndrome.

Grant Number: 7R01HL165725-04
NIH Institute/Center: NIH
Principal Investigator: Maria Pilar Alcaide Alonso