Neuritin Is Required for T Regulatory Cell-Mediated Suppression of the Long-Lived Plasma Cell Niche

Abstract T Regulatory cells (Tregs) are critical mediators of the immune system both during active immune responses and in the maintenance of immune homeostasis. Neuritin, a highly conserved gpi-anchored protein, has been shown to regulate Treg maintenance and function in vivo. Recent data demonstrates a critical role for Tregs in the survival of bone marrow (BM) resident plasma cells (BMPCs), and that CTLA-4 expressed on Tregs limits the BMPC niche. However, the molecular mechanisms by which Tregs in the bone marrow both promote BMPC survival and limit the niche space are unknown. Here we demonstrate that Treg intrinsic neuritin levels correlate with high expression of CD44, and that activation increases the population of CD44 expressing cells in neuritin-high Tregs. This suggests that neuritin positively regulates the induction of effector Tregs. However, there is not a significant difference in the percentage of Tregs in the BM of wild type (WT) vs neuritin knock-out (KO) mice. Interestingly, in neuritin KO BM, there is a significant increase in the % of B220-ve CD138+ve BMPCs, implying that neuritin negatively regulates the BMPC pool. Previously published data from our collaborators show that CD28 is required for BMPC survival. This occurs via interaction with BM resident CD80/86 expressing dendritic cells (DCs). CTLA-4, possibly from Tregs, can also bind CD80/86 on DCs. This may sequester the survival signals to BMPCs from CD80/86. This leads to a model wherein neuritin-mediated regulation of bone marrow Treg effector functionality negatively regulates the BMPC survival niche. With the ability to target CTLA-4 with novel immunotherapeutic strategies, this understanding may allow us to enhance vaccine design and augment humoral immunity.