The Human Thymus Is Enriched for Autoreactive B Cells

Abstract

The human thymus has been shown to host B cells, which have been implicated in presentation of autoantigens for negative selection of T cell progenitors. Although these Ags are thought to be taken up through their surface Igs, data on thymic Ig gene repertoires are limited and reactivity to autoantigens has not been demonstrated. We therefore studied the Ig gene repertoires and reactivity to autoantigens of single-sorted B cells from pediatric thymus, and compared these with mature B cells from fetal and pediatric bone marrow. Nearly all B cells in thymus were mature and displayed an Ig gene repertoire that was similar to pediatric bone marrow. Fetal mature B cells predominantly used proximal V, D, and J genes, and their Abs were highly reactive to dsDNA. In contrast, thymic B cells were enriched for autoreactive clones that showed increased specificity to peptide autoantigens. Thus, most B cells in the thymus are resident rather than developing, and are enriched for autoantigen binding. These features support current models for a role of thymic B cells in presentation of autoantigens to developing T cells during negative selection.

Decreased IL7Rα and TdT expression underlie the skewed immunoglobulin repertoire of human B-cell precursors from fetal origin

“…In line with previous observations 1 16 17 20 21 24 25 27 34 , mature B cells (CD19+CD20+CD10-IgM+IgD+) in fetal BM showed more frequent usage of V h 1-2, D h 7-27, J h 2 and J h 3 genes than pediatric B cells ( Supplementary Fig. 1 ) 23 . This IGH gene usage was typical for early development, because the IGH repertoire in B cells from neonatal cord blood was more similar to pediatric than to fetal B cells ( Supplementary Fig.…”

“…First, we assessed the repertoire in single-sorted naive mature B cells, thereby avoiding potentially preferential PCR-based amplification of V genes. Consequently, we obtained an unbiased view of the naive B cell-repertoire 23 . Secondly, we amplified IGH and IGK gene rearrangements from early precursors that had not yet been selected for in-frame rearrangements 35 .…”

“…Several studies have addressed the Ig gene repertoire in human fetuses, and reported restricted repertoires due to shorter CDR3 regions in IGH . This restriction was the result of limited N-nucleotides in the junctions and more frequent usage of the relatively short D h 7-27, J h 2 and J h3 genes 1 2 14 15 16 17 18 19 20 21 22 23 . Finally, the D h -proximal V h 6-1 and V h 1-2 genes appear to be more frequently used in fetal B cells 1 24 25 26 27 .…”

The Usage of Human IGHJ Genes Follows a Particular Non-random Selection: The Recombination Signal Sequence May Affect the Usage of Human IGHJ Genes

“…We analyzed the usage frequency of the 6 IGHJ gene families in BCR-H repertoires from 19 published articles (Forconi et al, 2010;Racanelli et al, 2011;Ippolito et al, 2012;Prabakaran et al, 2012;Yin et al, 2013;Briney et al, 2014;Mroczek et al, 2014;Lecerf et al, 2015;Martin et al, 2015Martin et al, , 2016Zhang et al, 2015Zhang et al, , 2017Guo et al, 2016;Kerzel et al, 2016;Rother et al, 2016;Tan et al, 2016;Liu et al, 2017;Roy et al, 2017;Hirokawa et al, 2019; Supplementary Table 8). Overall, subjects included healthy volunteers of different ages (2 months to 87 years) and patients with different pathological conditions, including SLE, primary biliary cholangitis (PBC), colorectal adenoma and carcinoma (CRC), celiac disease (CD), congenital heart disease, atopic dermatitis, hepatitis C virus infection, rheumatoid arthritis, and primary immune thrombocytopenia, as well as in humanized NOD-scid-IL2R gamma (null) mice.…”

Les lymphocytes B thymiques : plus que de simples spectateurs de la lymphopoïèse T

“…Comparés aux LB périphériques, une fréquence plus élevée de mutations est retrouvée dans les CDR (complementarity determining regions) des LB thymiques, et leurs séquences suggèrent un biais de reconnaissance vers des autoantigènes (avec une forte homologie avec des anticorps poly-réactifs ou anti-gangliosides) [19]. En 2016, la génération d'anticorps à partir de LB naïfs thymiques, par Rother et al, a confirmé le caractère autoréactif plus important envers des antigènes protéiques, des LB thymiques par rapport à leurs équivalents de la moelle osseuse [30]. Ces LB autoréactifs peuvent capter efficacement différents autoantigènes au moyen de leur BCR et présenter des peptides dérivés de ces autoantigènes, par l'intermédiaire du CMH-II, aux thymocytes en développement [10,17,21].…”