B cell expression of the enzyme PexRAP, an intermediary in ether lipid biosynthesis, promotes antibody responses and germinal center size

The qualities of antibody (Ab) responses provided by B lymphocytes and their plasma cell (PC) descendants are crucial facets of responses to vaccines and microbes. Metabolic processes and products regulate aspects of B cell proliferation and differentiation into germinal center (GC) and PC states as well as Ab diversification. However, there is little information about lymphoid cell-intrinsic functions of enzymes that mediate ether lipid biosynthesis, including a major class of membrane phospholipids. Imaging mass spectrometry (IMS) results had indicated that concentrations of a number of these phospholipids were substantially enhanced in GC compared to the background average in spleens. However, it was not clear if biosynthesis in B cells was a basis for this finding, or whether such cell-intrinsic biosynthesis contributes to B cell physiology or Ab responses. Ether lipid biosynthesis can involve the enzyme PexRAP, the product of theDhrs7bgene. Using combinations of IMS and immunization experiments in mouse models with inducibleDhrs7bloss-of-function, we now show that B lineage-intrinsic expression of PexRAP promotes the magnitude and affinity maturation of a serological response. Moreover, the data revealed aDhrs7b-dependent increase in ether phospholipids in primary follicles with a more prominent increase in GC. Mechanistically, PexRAP impacted B cell proliferation via enhanced survival associated with controlling levels of ROS and membrane peroxidation. These findings reveal a vital role of this peroxisomal enzyme in B cell homeostasis and the physiology of humoral immunity.