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CD4+ T-lymphocytes exhibit biphasic kinetics post-myocardial infarction
Vinay Kumar1,2, Sumanth D Prabhu3, Shyam S Bansal1,2,4
1Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Insights
CD4+ T-cells play a dual role in heart conditions. Initially aiding healing after myocardial infarction (MI), they later worsen heart failure (HF) by promoting cardiac remodeling. Targeting these cells during HF could be a new treatment.
Area of Science:
- Immunology
- Cardiovascular Biology
- Pathophysiology
Background:
- CD4+ T-cells are crucial for wound healing post-myocardial infarction (MI).
- However, their role in chronic ischemic heart failure (HF) and left-ventricular (LV) remodeling is complex and not fully understood.
- Distinct T-cell activation patterns may occur during acute MI versus chronic HF.
Purpose of the Study:
- To investigate the temporal dynamics and phenotypic characteristics of cardiac CD4+ T-cells during MI and HF.
- To determine the specific role of CD4+ T-cells in promoting LV remodeling and dysfunction during chronic ischemic heart failure.
- To explore the therapeutic potential of targeting CD4+ T-cells in HF.
Main Methods:
- Flow cytometry was used to analyze cardiac CD4+ T-cell populations at different time points post-MI and during HF.
- CD4-iDTR mice were generated to enable conditional depletion of CD4+ T-cells using diphtheria toxin (DT).
- Echocardiography was performed to assess left-ventricular remodeling (volumes, ejection fraction) in control and T-cell depleted mice.
Main Results:
- Cardiac CD4+ T-cells exhibited biphasic transmigration patterns: a rapid early response post-MI and a second, sustained activation phase during HF.
- During HF, CD4+ T-cell levels were significantly elevated (approximately 20-fold) compared to sham-operated controls, affecting multiple T-cell subsets.
- Depletion of CD4+ T-cells during chronic HF significantly attenuated LV remodeling (reduced end-diastolic and end-systolic volumes) and preserved ejection fraction.
Conclusions:
- The CD4+ T-cell response during chronic heart failure differs from that during acute myocardial infarction and actively drives pathological left-ventricular remodeling.
- Sustained CD4+ T-cell activation in HF promotes progressive cardiac dysfunction.
- Temporal immunomodulation of CD4+ T-cells represents a promising therapeutic strategy for treating ischemic heart failure.
Abstract:
CD4+ T-cells facilitate wound healing post-myocardial infarction (MI) but promote left-ventricular (LV) remodeling during ischemic heart failure (HF; 8 weeks post-MI). Therefore, it is critical to understand if sustained CD4+ T-cell activation leads to this pathological response, or if phenotypically different T-cells are activated during MI vs. HF. Using flow cytometry, we found that cardiac CD4+ T-cells exhibit two distinct patterns of transmigration. First pattern consisted of a rapid CD4+ T-cell response with maximal levels seen at 3 days post-MI which return to baseline by 14 days. However, during HF we observed a 2nd phase of activation and CD4+ T-cells were ∼20-fold higher in HF as compared to sham-operated mice. Importantly, these biphasic kinetics were observed with all major T-cell subsets such as Th1, Th2, Th17, and regulatory T-cells suggesting a global change. To determine the role of this 2nd peak of T-cell activation, CD4-iDTR mice were generated and treated with DT every 10 from 28 days post-MI to deplete CD4+ T-cells during chronic HF. While littermate control mice showed increased end-systolic and end-diastolic volumes (ESV and EDV) and decreased ejection fraction (EF) from 4 to 8 weeks post-MI, depletion of CD4+ T-cells in Cre + mice significantly blunted LV remodeling and inhibited progressive increases in the EDV and ESV, and reduction in EF. This suggests that CD4+ T-cell responses occurring during HF are different than those occurring during MI and promote LV remodeling and progressive cardiac dysfunction. Temporal immunomodulation of CD4+ T-cells could be a translatable modality for ischemic HF.
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