Positive and negative selection shape the human naive B cell repertoire
Jeff W. Chen, … , Laurence Menard, Eric Meffre
Jeff W. Chen, … , Laurence Menard, Eric Meffre
Published November 23, 2021
Citation Information: J Clin Invest. 2022;132(2):e150985. https://doi.org/10.1172/JCI150985.
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Research Article Autoimmunity Immunology

Positive and negative selection shape the human naive B cell repertoire

Abstract

Although 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 2 humanized mouse models, we demonstrate that there was strong skewing of the 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 observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II–restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.

Authors

Jeff W. Chen, Jean-Nicolas Schickel, Nikolaos Tsakiris, Joel Sng, Florent Arbogast, Delphine Bouis, Daniele Parisi, Ruchi Gera, Joshua M. Boeckers, Fabien R. Delmotte, Margaret Veselits, Catharina Schuetz, Eva-Maria Jacobsen, Carsten Posovszky, Ansgar S. Schulz, Klaus Schwarz, Marcus R. Clark, Laurence Menard, Eric Meffre

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Figure 1

Peripheral selection of autoreactive naive B cells requires the presence of an autologous thymus.

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Peripheral selection of autoreactive naive B cells requires the presence...
(A) Schematic diagram depicting the generation of 2 humanized mouse models. CD34+ HSCs were injected into the liver of NSG pups (NSG mouse model) or i.v. into adult mice, along with surgical implantation of a piece of autologous thymus under the kidney capsule (NSG + thymus mouse model). (B) Representative image of the engrafted human thymic organoid upon sacrifice of the humanized mouse. (C) Representative flow cytometric analysis of the frequency of human (h) CD45+, CD3+, and CD19+ cells, reflecting the extent of engraftment in the blood of humanized mice. Max, maximum; Q, quadrant.(D) Recombinant Abs cloned from mature naive B cells from HDs (n = 13), NSG humanized mice (n = 7), and NSG + thymus humanized mice (n = 7) were tested by ELISA for anti–HEp-2 cell reactivity. Dotted lines show the ED38 positive control. Horizontal lines show the cutoff OD405 for positive reactivity. For each individual or humanized mouse, the frequency of nonreactive (white area) and reactive (black area) clones is summarized in a pie chart below, with the total number of clones tested indicated in the centers. The frequencies of HEp-2–reactive and polyreactive mature naive B cells are summarized in E and G, respectively. Each symbol represents an individual or humanized mouse. Solid lines show the mean. The frequencies of (F) HEp-2–reactive and (H) polyreactive B cells and their evolution between the new emigrant/transitional and mature naive B cell stages in NSG and NSG + thymus humanized mice. (I) Human BAFF concentrations were measured by ELISA in the sera of nonengrafted NSG mice, NSG humanized mice, NSG + thymus humanized mice, and HDs. *P < 0.05 and ****P < 0.0001, by Mann-Whitney U test (E, G, and I).