Synthesis and fatty acid oxidation is not fully understood, as most cells utilize regulatory mechanisms that prevent this inefficiency. One possibility is that the availability of fatty acids from the extracellular environment in vivo might differ depending on the tissues where they reside therefore Tm cells continuously store lipids that can be utilized for fatty acid oxidation. The importance of fatty acid oxidation for Tm cells is bolstered by the observations that diminishing or enhancing AMPK, a positive regulator of fatty acid oxidation, decreases or increases formation of SKI-II site memory T cells. Further evidence supporting the importance of mitochondrial metabolism comes from the observation that increasing or decreasing glycolytic flux, which reciprocally modulates mitochondrial metabolism, results in enhanced or diminished generation of memory T cells, respectively. Although there is mounting evidence that mitochondrial metabolism maintains the memory T cell phenotype, it remains unknown why this is and whether mitochondria participate in cell signaling necessary to establish the memory T cell phenotype. Similar to T cells, B cells also undergo major transitions in their metabolic profiles as 
they transition from nave quiescent cells to anabolic proliferative cells. Upon activation, B cells Immunity. Author manuscript; available in PMC 2016 March 17. Weinberg et al. Page 12 greatly enhance glucose and glutamine metabolism DMXB-A web during clonal expansion comparable to T cells. Along with these changes in metabolism, B cell receptor activation is regulated by ROS. Specifically, BCR ligation stimulates PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19850903 calcium release into the cytoplasm that promotes ROS production and inactivation of receptor-coupled phosphates, allowing for activation of downstream signaling pathways. Depending on the magnitude of the ROS pulse, there is increased duration of BCR signaling and enhanced activation of downstream signaling pathways. Initially, the cytosolic NADPH oxidases were surmised to be source of ROS for B cell function. However, new data from primary B cells suggests that early ROS production by NADPH oxidases is dispensable for BCR signaling. Instead, long term elevations in ROS levels, potentially driven by increased production of mitochondrial ROS, are required for downstream BCR signaling and cellular proliferation in response to BCR cross-linking. Along with ROS signaling, new studies also suggest that other mitochondrial-derived molecules have important roles in B cell activation and effector function. Recent studies have suggested that plasma cells produce increased levels of phospholipids when compared to nave B cells, and plasma cell differentiation is dependent on mitochondrial citrate conversion to acetyl-CoA and oxaloacetate in the cytoplasm. Although the evidence is incomplete, these new studies indicate that mitochondrial metabolism is altered during B cell activation and plasma cell development. Future studies will delineate whether mitochondria metabolism is essential in driving differential B cell function in a manner similar to T cells. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Concluding remarks The mammalian immune response is extremely complex, requiring the coordination of multiple organ systems and a large variety of cells within those organs. These immune cells are so effective because they are able to rapidly respond to the stress of infection through activation and often proliferation, differentiation,.Synthesis and fatty acid oxidation is not fully understood, as most cells utilize regulatory mechanisms that prevent this inefficiency. One possibility is that the availability of fatty acids from the extracellular environment in vivo might differ depending on the tissues where they reside therefore Tm cells continuously store lipids that can be utilized for fatty acid oxidation. The importance of fatty acid oxidation for Tm cells is bolstered by the observations that diminishing or enhancing AMPK, a positive regulator of fatty acid oxidation, decreases or increases formation of memory T cells. Further evidence supporting the importance of mitochondrial metabolism comes from the observation that increasing or decreasing glycolytic flux, which reciprocally modulates mitochondrial metabolism, results in enhanced or diminished generation of memory T cells, respectively. Although there is mounting evidence that mitochondrial metabolism maintains the memory T cell phenotype, it remains unknown why this is and whether mitochondria participate in cell signaling necessary to establish the memory T cell phenotype. Similar to T cells, B cells also undergo major transitions in their metabolic profiles as they transition from nave quiescent cells to anabolic proliferative cells. Upon activation, B cells Immunity. Author manuscript; available in PMC 2016 March 17. Weinberg et al. Page 12 greatly enhance glucose and glutamine metabolism during clonal expansion comparable to T cells. Along with these changes in metabolism, B cell receptor activation is regulated by ROS. Specifically, BCR ligation stimulates PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19850903 calcium release into the cytoplasm that promotes ROS production and inactivation of receptor-coupled phosphates, allowing for activation of downstream signaling pathways. Depending on the magnitude of the ROS pulse, there is increased duration of BCR signaling and enhanced activation of downstream signaling pathways. Initially, the cytosolic NADPH oxidases were surmised to be source of ROS for B cell function. However, new data from primary B cells suggests that early ROS production by NADPH oxidases is dispensable for BCR signaling. Instead, long term elevations in ROS levels, potentially driven by increased production of mitochondrial ROS, are required 
for downstream BCR signaling and cellular proliferation in response to BCR cross-linking. Along with ROS signaling, new studies also suggest that other mitochondrial-derived molecules have important roles in B cell activation and effector function. Recent studies have suggested that plasma cells produce increased levels of phospholipids when compared to nave B cells, and plasma cell differentiation is dependent on mitochondrial citrate conversion to acetyl-CoA and oxaloacetate in the cytoplasm. Although the evidence is incomplete, these new studies indicate that mitochondrial metabolism is altered during B cell activation and plasma cell development. Future studies will delineate whether mitochondria metabolism is essential in driving differential B cell function in a manner similar to T cells. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Concluding remarks The mammalian immune response is extremely complex, requiring the coordination of multiple organ systems and a large variety of cells within those organs. These immune cells are so effective because they are able to rapidly respond to the stress of infection through activation and often proliferation, differentiation,.