Positive and negative selection shape the human naïve B cell repertoire

While negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using two humanized mouse models, we demonstrate that there is strong skewing of expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that in healthy donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymic-derived regulatory T cells (Tregs) and MHC class II-restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on their B cells in rare bare lymphocyte syndrome patients or prevention of self-antigen presentation via HLA-DM inhibition in humanized mice result in the production of autoreactive naive B cells. These latter observations suggest that Tregs repress autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerges in which both positive and negative selection shape the human naive B cell repertoire and that each process is mediated by fundamentally different molecular and cellular mechanisms.