Research
T Cell Lymphopenia
T lymphopenia, defined as a reduction in circulating T-cell numbers, occurs in a subset of patients following MI and is associated with worse clinical outcomes. Despite its prognostic significance, the mechanisms by which MI induces T lymphopenia remain poorly understood. We have demonstrated that MI activates the hypothalamic–pituitary–adrenal (HPA) axis, resulting in increased glucocorticoid secretion. Elevated glucocorticoids promote redistribution of circulating lymphocytes to the bone marrow, leading to T lymphopenia. In addition, glucocorticoids induce thymocyte apoptosis and impair T-cell lymphopoiesis, further exacerbating T lymphopenia. We are currently investigating the therapeutic potential of targeting T lymphopenia to improve myocardial repair after MI using pharmacological approaches and mice with T cell–specific deletion of the glucocorticoid receptor.
Aged-Associated Thymic Involution and MI
Aging is associated with a poorer prognosis following MI, but the underlying mechanisms remain incompletely understood. With advancing age, the thymus undergoes profound involution, resulting in impaired T-cell generation and function. T cells play an essential role in regulating cardiac wound healing following acute ischemic injury. We hypothesize that age-related thymic involution aggravates cardiac remodeling after MI by limiting T cell count and response. We showed that aging diminishes thymic output, reduces naive t cells, promotes memory T-cell accumulation, and impairs thymic regeneration. Currently, we are using surgical and pharmacological approaches to regrow the involuted thymus and see if these interventions can improve post-MI cardiac recovery.
Innate Immune Memory and MI
Although innate immunity has been previously described as void of immunological memory, it has recently been shown that innate immune cells can develop nonspecific memory to certain stimuli. These various stimulants, such as lipopolysaccharides (LPS), β-glucan, and the Bacillus Calmette–Guérin (BCG) vaccine, can cause metabolic reprogramming of immune cells leading to two arms of innate immune memory: trained immunity and immune tolerance. Trained immunity is described as a heightened inflammatory response that can lead to enhanced pathogen clearance and tissue inflammation. Immune tolerance is noted by a repressed inflammatory response that may prove beneficial in chronic inflammatory conditions. In the setting of myocardial infarction (MI), inflammation plays a vital but possibly detrimental role and remains a major obstacle in the ability of the cardiac tissue to recover. We study how induction of innate immune memory can modulate the recovery of the heart following a MI, ranging from fibrotic scar formation, function and infarct area size.