Plasma Cells (PCs; B220lowCD138hiBlimp1+Ig+) in LN and spleen were shown to be the major source of B cell lineage IL-10, and absence of PCs worsens EAE (Matsumoto, Immunity: 2014). This implies that PCs exhibit Breg activity and in prior 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 expressing or lacking PCs. BALB/c islets were transplanted into chemically diabetic PC-KO B6 mice (Blimp1-fl/fl CD19-Cre+) in which BLIMP-1 (essential transcription factor for PC differentiation) is congenitally deleted in B cells or into cre-neg Control mice. Anti-TIM-1 treatment (250 ug ip d1-,0,5) was more effective in PC-KO than in Control mice (66% vs. 26% >100d GS p<0.05). Thus, while anti-TIM-1 requires Bregs, it does not require PCs and, in fact, acts better in their absence.

This prompted us to re-examine the EAE model where the regulatory role of PCs was first identified. Surprisingly, in our hands, the severity of EAE (induced by MOG35-55+CFA) was dramatically reduced in PC-KO vs. Control mice (Blimp1fl/fl CD19-Cre-neg) (p<0.05). In both EAE and transplant models, PC-KO mice had >95% decrease in PCs. Moreover, B cell cytokine expression (by flow) revealed a 1.4 fold increase in IL-10, and >2-fold decrease in IFNγ and IL-17 expression in PC-KO vs. cre-neg. Control mice.

To explain the discrepancy between our data and Matsumoto et al, we re-examined PC cytokine expression. WT B6 mice were alloimmunized with BALB/c splenocytes and cytokine expression by splenic PCs was assessed by flow after 10d. As expected, PCs were enriched for IL-10 (30% IL-10+). However, we made the novel discovery that PCs are also highly enriched for expression of IFNγ (25%) and IL-17 (16%). PCs also had higher inflammatory cytokines in draining LN 14d after EAE induction (IFNγ 14%; IL-17 44%). By comparison, the frequency of cytokine expressing B cells is: IL-10 4%; IFNγ 2%, and IL-17 5%.

Collectively, our results indicate that PCs are not necessary for Breg activity in either autoimmunity or transplantation. In fact, PC deficiency can result in discordant outcomes depending on their relative prevalence of coexisting immunosuppressive vs. proinflammatory cytokine expression.

CITATION INFORMATION: Song Z., Zhou Y., Ding Q., Rothstein D. The Regulatory Role of Plasma Cells (as Bregs) is Counterbalanced by a NOVEL Inflammatory Role in Murine Transplant and Autoimmune Models Am J Transplant. 2017;17 (suppl 3).

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