Plasma cells are not necessary for regulatory B cells and preventing their differentiation markedly prolongs allograft survival

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Abstract Plasma Cells produce Abs. Recently, PCs were reported to be the major source of B-cell IL-10, and absence of PCs worsened EAE, implying that PCs underlie “Breg” activity. To test the hypothesis in transplantation, we transplanted Bc islets into chemically diabetic B6 Blimp-1fl/flCD19-Cre+/− (PCKO) mice. Surprisingly, allograft survival (GS) was prolonged by ~42% in untreated PCKO vs. Cre-neg Ctl recipients (Mean GS: 27 vs. 19d; p<0.05). 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 (MOG35–55 induced) was dramatically reduced in PCKO vs. Ctl mice (p<0.05). These unexpected results suggested that PCs are not essential for Breg activity, but might actually promote EAE and allograft rejection. These improved results do not appear to be mediated simply by loss of Ab production, since EAE is worse in the complete absence of B cells. To investigate the differences between our own and published results, we examined B cells from PCKO mice and found a 1.4-fold ↑ in IL-10+and >2-fold ↓ in IL-17+ B cells vs. Ctl mice (intracellular staining; flow cytometry). Moreover, CD4+T cells from PCKO mice exhibited a ~2.5× ↑ in IL-10 and ~2× ↓ in IL-17. Therefore, we examined cytokine expression by splenic PCs in alloimmunized Blimp-1-YFP reporter mice. While PCs are enriched for IL-10 expression (42±3%), they are also highly enriched for IL-17 (50 ±9%). 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.