Date: Tuesday, June 4, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Classically, B cells differentiate into Ab-secreting plasma cells (PCs; B220lowCD138hiBlimp1+Ig+) providing humoral immunity. B cells can also inhibit or promote immune responses through the activity of IL10+ Bregs and IFNγ+ B effectors (Beff). Recently, PCs were shown to be the major source of B-cell lineage IL10, and PC deficiency(PCko) worsened EAE (Matsumoto, Immunity: 2014). This suggest that PCs underlie most “Breg” activity and in prior Breg studies, classical B cells likely differentiate into PCs that actually mediate Breg function. To test this hypothesis, we examined the ability of anti-TIM-1 (which acts through induction of IL-10+ Bregs) to prolong islet allograft survival (GS) in recipients lacking PCs.
*Methods: To examine the role of PCs, BALB/c islets were transplanted into chemically (Streptozotocin, STZ) induced diabetic PCko B6 mice (Blimp1fl/flCD19-Cre+, congenital deletion of Blimp1, a transcription factor essential for PC differentiation; leading to >95% reduction in PCs), or into Cre-neg Control (Ctl) mice. IFNγ and IL10 were examined in splenic PCs, conventional CD19+B and CD4+ T cells from alloimmunized recipients (detected by intracellular flow cytometry).
*Results: Surprisingly, GS was prolonged by 42% in untreated PCko vs. control recipients (MST 27d vs. 19d; p<0.05). Moreover,anti-TIM-1 (RMT1-10; 250 ug ip d1-,0,5) treatment was more effective in PCko than Ctl mice (66% vs. 26% GS>100d; p<0.05). Thus, while anti-TIM-1 requires Bregs, it does not require PCs and, in fact, works better in their absence. Moreover, CD4+T cells from PCko mice exhibited a ~2.5× increase in IL10 and ~2×decrease in IFNγ expression vs. Ctl mice. This prompted us to re-examine the EAE model where regulatory PCs was first identified. Surprisingly, in our hands, the severity of EAE (induced by MOG 35-55 peptide +CFA) was dramatically reduced in PCko vs. Ctl mice (p<0.05). To investigate this discrepancy, we further examined cytokines expression by splenic PCs from alloimmunized B6 mice by Flow. As expected, PCs were enriched for IL10 (~38%+). However, we made the discovery that PCs are also highly enriched for IFNγ (~25%+). (By comparison, ony 4% of whole B cells express IL-10 and 2% express IFNγ). Furthermore, ~50% PCs express TIM-4, which we previously identified as an inclusive marker for IFNγ-expressing Beff cells that promote transplant rejection (Ding, JI, 2017). (By comparison, only ~8% conventional B cells are TIM-4+).
*Conclusions: Our results indicate that PCs are not necessary for Breg activity in either autoimmune or transplant models. Moreover, they suggest that PCs expressing pro-inflammatory cytokines promote allograft rejection and autoimmunity and can offset the loss of regulatory IL10+ PCs. PC-deficiency might result in discordant outcomes depending on the relative balance of anti-inflammatory vs pro-inflammatory PCs. This hypothesis is being directly tested in novel mice we developed that exhibit PC-specific KO of either IL10 or inflammatory cytokines.
To cite this abstract in AMA style:Ding Q, Zhou Y, Song Z, Zeng L, Rothstein D. IL-10+ Plasma Cells Are Not Required for Breg Activity and Are Counterbalanced by Novel Pro-Inflammatory Plasma Cells [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/il-10-plasma-cells-are-not-required-for-breg-activity-and-are-counterbalanced-by-novel-pro-inflammatory-plasma-cells/. Accessed September 25, 2020.
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