Injury polarized CD4+ T cells orchestrate redox and unfolded protein responses to promote cardiac repair after myocardial infarction.

Myocardial infarction (MI) initiates a wound-healing response where immune cells shape inflammation, tissue repair, and long-term remodeling. Although CD4+ T cells are increasingly recognized as contributors to post-MI healing, the transcriptional reprogramming defining their early pro-reparative functions remains incompletely resolved. Here, RNA sequencing of cardiac CD4+ T cells isolated 1 week after MI found that a substantial post-MI transcriptional fraction lay outside canonical cytokine-induced T helper subset polarization, including type 1 T helper cell (Th1), Th2, Th17, nature-occurring CD4+ regulatory T cell (nTreg), and peripherally induced Treg (iTreg) reference transcriptomic programs. Instead, this response was organized into a distinct CD4+ Th tissue injury-polarized (CD4+/TIP) transcriptomic module enriched for extracellular matrix organization, adhesion, vascular, and developmental programs, with a coordinated downregulated arm involving RNA metabolism, chromatin regulation, and protein catabolic processes. Within the CD4+/TIP population, MI induced and polarized at least 10 transcriptionally distinct CD4+ Th subsets at 1 week post-MI. Integration with curated transcription factors, epigenetic, reduction-oxidation (redox), and unfolded protein response (UPR) datasets identified a stress-adaptive architecture, in which regulatory subsets and the CD4+/TIP population shared redox attenuation features, while the CD4+/TIP state showed the strongest coupling to reparative tissue interaction programs, predominant Activating Transcription Factor 6 (ATF6)-aligned UPR structure, restrained proteostasis related outputs, and an innate-adjacent immune and secretome signature enriched for complement-associated, inflammatory recruitment, and extracellular communication genes. These findings identify a specific MI-associated CD4+ T-cell transcriptomic state during early MI inflammation and tissue repair. They establish a coordinated framework in which redox control, UPR, and tissue-injury-polarized CD4+ T-cell immune programs converge outside traditional Th and Treg lineages, offering new targets for CD4+ T-cell-mediated tissue repair after MI.