Humoral memory is central to the capacity of vaccines to protect against microbes and is a key feature of adaptive immunity. A major determinant of this process is the potency with which germinal center (GC) reactions foster the differentiation and maintenance of memory B cells, which in turn are critical determinants of recall responses. Much has been learned about the potential fates of a B cell after its activation, including vital contributions of BCR affinity for Ag and other global features of GC reactions, but remarkably little is known about how signaling within the B cell impacts memory. Accumulating evidence with in vitro manipulations as well as mouse model systems provides indications of a regulatory inter-play of local physiology (e.g., nutrient supply) with signaling in cells of the immune system and their fate or functional characteristics. The unique biology of B cells and memory implies that they use novel metabolic mechanisms. However, very little is known about metabolic regulation for the B lymphoid lineage and especially not for B cell memory or the persistence of adequate concentrations of Ab. AMP-activated kinase (AMPK), the target of anti-diabetic agents such as metformin, is central to regulation of the balance between energy generation versus utilization in bio-synthesis. We have found that the predominant isoform of AMPK in B cells, AMPK?1, promoted the capacity for a recall Ab response in a B cell-intrinsic role. We also developed evidence of a pathway parallel to AMPK, on which an ADP-ribosyl transferase, PARP14, promotes increases in glycolysis, glucose oxidation, and B cell survival. Moreover recall Ab responses of several Ab isotypes depended on PARP14. These and further findings lead us to hypothesize that AMPK? promotes the generation or maintenance of Ag-specific memory B cells, and that this function is exerted at least in part through promotion of metabolic fitness [fatty acid oxidation (FAO) as well as glycolysis and glucose oxidation]. The research also will address an unresolved paradox from key studies of the central paradigm of CTL memory, in which (FAO) is associated with memory fate while glycolysis ties to effector-like phenotype. The conundrum is that the balancing act was attributed to AMPK activity, but this kinase promotes both FAO and glycolysis. We will test the hypothesis that differential regulation of these forms of energy generation is based on mTOR-regulated activity of HIF-1, a transcription factor that may directly repress FAO alongside its activation of glycolysis. To test the impact of AMPK activity on humoral recall, and elucidate a mechanism by which AMPK-driven metabolic pathways can be balanced, we have three specific Aims.
The first (Aim 1) is to establish a specific B lineage- intrinsic function for the key metabolic regulator, AMPK, in memory for humoral immunity. Moreover, we plan to test a model in which HIF-1 is integrated with AMPK in setting B cell metabolic balance and recall Ab responses (Aim 2). Finally, we will evaluate if mTOR is an effector of AMPK and HIF-1 in B cells and humoral memory (Aim 3). The expected outcome of the proposed studies is that we will uncover novel roles for AMPK and HIF-1 in determining the metabolic profile in B cells and functional outcome in humoral immunity.
The ability to maintain or renew high enough concentrations of antibodies protects us against disease caused by various microbes and is central to vaccine efficacy, yet also can be part of how many immune-mediated diseases undermine our health. These long-lived antibody responses are produced after one class of white blood cells is activated, interacts with other classes of cell, differentiates to new fates, and persists for year. This proposal seeks support to allow us to identify novel signaling mechanisms that regulate how well B lineage cells are directed toward long-term memory.
|Raybuck, Ariel L; Cho, Sung Hoon; Li, Jingxin et al. (2018) B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity. J Immunol 200:2627-2639|
|Boothby, Mark; Rickert, Robert C (2017) Metabolic Regulation of the Immune Humoral Response. Immunity 46:743-755|