Laboratory for Lymphocyte Differentiation

Antibodies (Abs) are produced by terminally differentiated plasma cells (PCs) and have distinct effector functions depending on their isotype. While the majority of PCs generated in the secondary lymphoid tissues (induction site) die within days after formation (termed short-lived PCs; SLPCs), a small majority persist for months, years, or even decades. These long-lived PCs (LLPCs) are typically found in the bone marrow (effector site). Clarifying the key determinants of plasma cell persistence is important to regulate antibody longevity in vaccine and auto-immune settings. Since LLPCs are lodged in a location distinct from their site of generation, two conceptual models (induction site and effector site models) have been proposed to determine the persistence of plasma cells. According to the induction site model, heterogeneity of SLPCs are created at their generation site, for instance, depending on the amount of T cell help. Such variables may then instruct the longevity of plasma cells.

To address whether the induction site model is indeed operating or not, we traced newly generated plasma cells at the induction site and those just newly arriving at the bone marrow (effector site). We found that, among newly generated IgG plasma cells, integrin b7hi marks plasma cells predisposed to home to the bone marrow, whereas integrin b7lo cells remain in secondary lymphoid organs. Mechanically, this egress-prone fraction had a higher expression of the KLF2 transcription factor, the loss of which resulted in defective egress by downregulating S1PR1 and CD11b. Hence, the KLF2 expression level in IgG plasma cells at the induction site is one of the key factors that determine antibody durability by regulating the migration program.