Dual Response to IL-21 and IFN-Alpha Reveals Human B-Cell Precursors With Multiple Differentiation Potentials

Immunological memory is essential for effective immune protection upon antigen rechallenge. Memory B cells encompass multiple subsets, heterogeneous in terms of phenotypes, origins and precursors, anatomical localization, and functional responses. B-cell responses are conditioned by micro-environmental signals, including cytokines. Here, we analyzed in vitro the effects of two cytokines implicated in B-cell differentiation, interferon-alpha (IFN-α) and interleukin (IL)-21, on the early functional response of four different mature B-cell subsets (IgD+ CD27- naive, IgD+ CD27+ unswitched, IgD- CD27+ switched and double-negative B cells). The dual response of naive and memory B cells to IL-21 allowed us to uncover a unique IgD+ CD27- CD10- B-cell population characterized by the expression of marginal zone B-cell markers CD45RB and CD1c (referred to as NARB+). Similar to memory B cells, NARB+ cells displayed a pre-activated state, allowing them to rapidly differentiate into plasmablasts upon innate signals. However, this population also maintained its susceptibility to IL-21 activation-induced apoptosis similarly to the naive compartment. Both in-depth phenotypic analysis of circulating B cells, and identification of these cells in spleen, tonsil, and gut-associated lymphoid tissues, suggested that NARB+ could be uncommitted precursors of different developmental pathways including human marginal zone-like B cells (MZB). In this regard, we showed that patients with primary Sjogren’s syndrome exhibited a severe reduction of IgD+CD27+ MZB-like cells associated with a diminution of the NARB+ subset suggesting a developmental relationship.