Investigation of the plasma cell compartment of mice deficient in both E- and P-selection: Implications for plasma cell differentiation and function.

摘要

The formation of terminally differentiated antibody secreting plasma cells represents the critical final step in B cell differentiation. In this thesis, we demonstrate that IgG plasma cells constitute a significant fraction of cervical lymph node cells from mice deficient in both E- and P-selectin (E/P −/−) and these cells can be purified by phenotype. These IgG plasma cells exhibited upregulated cell surface expression of multiple adhesion molecules. In addition, the plasma cells interacted strongly with E-selectin, but poorly with P-selectin, despite elevated levels of PSGL-1. The interaction of plasma cells with E-selectin, but not P-selectin, correlated with elevated FucT-VII mRNA levels, but selective downregulation of C2GlcNAcT-I levels, compared to B cells. Additionally, we show that several plasma cell subsets, including significant numbers of B220-positive and B220-negative plasma cells, are concurrently present in the lymph nodes, spleen, and bone marrow of E/P −/− mice. Examination of the chemotactic responsiveness of plasma cell subsets reveals that migration towards CXCL12 is primarily limited to the B220-lo subset regardless of current tissue localization. Although B220-negative plasma cells do not migrate efficiently in response to CXCL12, these cells do express substantial surface protein for the CXCL12 receptor, CXCR4. Interestingly, the B220-negative plasma cells also expressed mRNA for the chemokine receptors CCR4 and CCR9. Furthermore, utilizing microarray analysis, we demonstrate the highly specialized genetic profile of terminally differentiated plasma cells. The plasma cells displayed an upregulation, induction, or a selective retention of a unique group of transcription factors, including members of the AP-1, NF-κB, and NFAT families. The plasma cells also displayed a downregulation of several RNA polymerase I related factors, and exhibited a downregulation of TATA box binding protein. Plasma cells displayed an upregulation of two factors normally associated with positioning of neuronal cells, reelin and neuropilin-1. Collectively, these studies provide insight into the complexity of the plasma cell compartment, plasma cell adhesion and migration, and the gene expression changes important in plasma cell function.