Myocardial infarction (MI)-induced heart failure is the leading cause of morbidity and mortality in the United States. About one in four MI patients will progress to develop chronic heart failure, which has a 5-year mortality rate of 40%. It is highly urgent to improve long-term outcomes of MI patients. Lymphopenia, a reduction in peripheral blood lymphocyte count (primarily due to T-cell loss), has consistently been shown to correlate with worse cardiac function and poor outcome in MI patients and is an independent marker to predict the prognosis. Unfortunately, how T lymphopenia occurs following MI and whether targeting T lymphopenia has therapeutic potential are largely unknown. Using the mouse MI-induced ischemic heart failure model, our preliminary data showed that MI-induced T lymphopenia may involve blood T-cell redistribution to the bone marrow and T cell development impairment. CD4+ T-cell activation is known to improve wound healing post-MI. Thus, persistent CD4+ T lymphopenia may reduce protective CD4+ T-cell response and compromise myocardial repair after MI. The goals of this proposal are: 1) to elucidate the underlying mechanisms that cause T lymphopenia following MI; and 2) to investigate whether inhibiting CD4+ T lymphopenia can serve as a therapeutic strategy. We hypothesize that MI induces T lymphopenia by both stimulating T-cell trafficking from blood to the bone marrow and impairing T lymphopoiesis; inhibiting CD4+ T lymphopenia improves post-MI cardiac repair. Three specific aims will address this novel hypothesis in a mouse ischemic heart failure model that combines multidisciplinary approaches. Specific Aim 1 will examine the mechanisms of blood T-cell trafficking to the bone marrow and alterations of distinct T-cell phenotypes and functions after MI. Specific Aim 2 will determine the mechanisms by which MI impairs T lymphopoiesis. Specific Aim 3 will examine the hypothesis that inhibiting CD4+ T lymphopenia would improve post-MI cardiac repair. Accomplishment of this proposal will provide new insights into T lymphopenia mechanisms in ischemic heart failure and may offer potential intervention strategies to improve the prognosis of heart failure patients.