Barth syndrome (BTHS) is a rare X-linked genetic disease classically characterized by cardiomyopathy, skeletal myopathy, and neutropenia. It is caused by mutations in the TAFAZZIN gene, which codes for the protein tafazzin (Taz), and this results in alterations in the level and molecular composition of the mitochondrial phospholipid cardiolipin with subsequent disruption in mitochondrial bioenergetics. Impaired mitochondrial function in BTHS patients contribute to increased risk of serious infections. B lymphocytes play a crucial role in the immune response and are responsible for humoral immunity through the production of antibodies. Intact mitochondrial function is essential to support B cell activation, function, and differentiation. Mesenchymal stem cells (MSCs) are immunoregulatory cells which can inhibit the activation of immune cells and they can suppress the immune response. Genetic modifications of MSCs have been shown to modulate their immunosuppressive properties. The aims of my project were to study the effect of Taz deficiency on B lymphocyte activation in both a human and a mouse model of BTHS and study the impact of Taz deficiency on the immunosuppressive function of MSCs and how this modulates B lymphocyte activity and differentiation. We observed that Epstein-Barr virus transformed control and BTHS lymphoblasts failed to enhance surface marker expression in response to lipopolysaccharide (LPS) stimulation and exhibited varied surface marker expression in response to cytosine phosphate guanine-deoxyribonucleic acid (CpG DNA) stimulation indicating that they are a poor model to study BTHS B cell immune function. However, Taz deficiency in B cells isolated from 3-month-old Taz knockdown (TazKD) mice exhibited a decreased ability to be activated by LPS or anti-cluster of differentiation 40 + interleukin-4. In addition, TazKD B cells exhibited reduced glycolysis and oxidative phosphorylation and this correlated with a reduction in their proliferation and immune function upon activation. We observed that MSCs isolated from TazKD mice exhibited an increase in glycolysis and this correlated with an enhanced proliferation and immunosuppressive properties. Finally, we showed that Taz deficient MSCs reduced proliferation and differentiation of LPS activated B cells. Our results highlight a novel role for Taz in the regulation of the immune system.