*Purpose: Plasma Cells (PCs) are the primary source of circulating antibodies. PCs were reported to be the major source of B-cell lineage IL-10, and absence of PCs worsened EAE (Shen, Nature, 2014), implying that PCs might underlie “Bregs” activity.

*Methods: We examined the role of PCs in murine islet allograft and EAE models using mice specifically unable to generate PCs due to a B cell specific KO of BLIMP-1 – a transcription factor essential for PC differentiation. BALB/c islets were transplanted into streptozocin-induced diabetic B6 BLIMP-1fl/flXCD19-Cre+/- (PC-KO) mice vs Cre-neg control (Ctl) mice. PC deletion was over 95% in spleen and LN. Islet graft survival (GS) in PC-KO vs. Ctl mice was examined in the absence of treatment or after anti-TIM-1, which acts through induction of IL-10+ Bregs. Additonally, we re-examined PC-KO vs. Ctl mice in the EAE model. Cytokine expression by splenic PCs was also examined using alloimmunized Blimp-1-YFP reporter mice. Recently we generated novel Blimp-1fl/flXhCD20-Tam-Cre+ mice, which are entirely normal until B cell-specific Cre translocates to the nucleus after Tamoxifen (TAM) treatment, resulting in Blimp-1 deletion. This prevents new PC generation and partially depletes (40%) of splenic short-lived PCs over time.

*Results: Surprisingly, GS was prolonged by ~42% in untreated PC-KO vs. Ctl recipients (mean 27d vs. 19d; p<0.05). Moreover, anti-TIM-1 treatment was more effective in PC-KO than Ctl mice (66% vs. 26% >100d GS; p<0.05). Thus, while anti-TIM-1 requires IL-10+ Bregs, it does not require PCs, and in fact, performs better in their absence. This prompted us to re-examine the EAE model. EAE severity was dramatically reduced in PC-KO vs. Ctl mice (d16 EAE scores: 1.30 ±0.3 vs. 3.9 ±0.3; p<0.05). Given this discrepancy with published results, we examined CD19+ B cells from PC-KO mice and found a 1.4-fold ↑ in frequency of IL-10 and >2-fold decreased frequency in IL-17 vs. Ctl mice. Moreover, CD4+T cells from PC-KO mice exhibited a ~2.5X ↑ in IL-10 and ~2X ↓ in IL-17 expression vs. Ctl mice. More remarkably, Blimp-1fl/flXhCD20-Tam-Cre+ mice exhibited markedly prolonged GS (>68 d) vs. Cre-only Ctls (all reject by 25d). However, B cell IL-10 in inducible PC-KO mice is similar to WT, suggesting that B increased B cell IL-10 is not the only mechanism underlying ↑ GS in the absence of PCs. Therefore, to further identify their potential modulatory role, we examined cytokine expression by splenic PCs in alloimmunized Blimp-1-YFP reporter mice. PCs were not only highly enriched for IL-10 expression (42±3%), but also for IL-17 (50 ±9%) – 10-100-fold higher than conventional B cells.

*Conclusions: Thus, PCs are not essential for Breg activity in either auto- or allo- immunity. We hypothesize preventing newly induced PCs may reduce immune responsiveness through the loss of potentially proinflammatory PCs. To further address these questions, we are now developing novel mice with PC-specific deletion of IL-10 or IL-17.

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