Collectively, the Frantz group describe an interesting observation in 2 different models of Treg depletion and 1 model of Treg activation: an altered abundance of these cells correlated with an altered macrophage phenotype and outcome post-MI. The study adds to the increasing evidence that heart macrophages are important in the evolution of heart failure, and reports a novel, potentially clinically important mechanism of how cardiac macrophage phenotype is steered. The data raise several interesting questions. For example, where and how do Tregs interact with myeloid cells? On the one hand, recent studies indicate that IL-10 is a critical homeostatic factor for macrophages. 16 On the other hand, the low absolute numbers of Tregs vis-a-vis myeloid cells in the infarct raises the question of whether additional interactions are important elsewhere. Can Tregs influence the supply of cells in other locations? Previously, Tregs were shown to influence the action of hematopoietic progenitors in the bone marrow. 17 Can Tregs interact with monocyte progenitors and change their phenotype before they enter inflamed tissues? Recent studies have shown that cell intrinsic factors, such as the orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1) expressed in monocytes regulate the emergence of Ly6Clow monocytes in blood and regulate the infarct macrophage phenotype. 4, 18 Another regulator of macrophage phenotype after MI is the master transcription factor IRF5 (interferon regulatory factor 5). 19 In light of the Treg data discussed above, it would be interesting to explore whether these mechanisms are coupled or independent. Overall, it is likely that the infarct macrophage phenotype results from an integration of multiple inputs, including cellintrinsic, systemic, and local factors. Going forward, we will need to identify viable avenues for a therapeutic intervention that modulates infarct inflammation and prevents post-MI heart failure. Additional work will show whether Treg activation is such an option for patients with MI.