BCR selection and affinity maturation in Peyer's patch germinal centres.

Huan Chen, Yuxiang Zhang, Adam Yongxin Ye, Zhou Du, Mo Xu, Cheng-Sheng Lee, Joyce K Hwang, Nia Kyritsis, Zhaoqing Ba, Donna Neuberg, Dan R Littman, Frederick W Alt

Nature 2020 Jun

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The antigen-binding variable regions of the B cell receptor (BCR) and of antibodies are encoded by exons that are assembled in developing B cells by V(D)J recombination1. The BCR repertoires of primary B cells are vast owing to mechanisms that create diversity at the junctions of V(D)J gene segments that contribute to complementarity-determining region 3 (CDR3), the region that binds antigen1. Primary B cells undergo antigen-driven BCR affinity maturation through somatic hypermutation and cellular selection in germinal centres (GCs)2,3. Although most GCs are transient3, those in intestinal Peyer's patches (PPs)-which depend on the gut microbiota-are chronic4, and little is known about their BCR repertoires or patterns of somatic hypermutation. Here, using a high-throughput assay that analyses both V(D)J segment usage and somatic hypermutation profiles, we elucidate physiological BCR repertoires in mouse PP GCs. PP GCs from different mice expand public BCR clonotypes (clonotypes that are shared between many mice) that often have canonical CDR3s in the immunoglobulin heavy chain that, owing to junctional biases during V(D)J recombination, appear much more frequently than predicted in naive B cell repertoires. Some public clonotypes are dependent on the gut microbiota and encode antibodies that are reactive to bacterial glycans, whereas others are independent of gut bacteria. Transfer of faeces from specific-pathogen-free mice to germ-free mice restored germ-dependent clonotypes, directly implicating BCR selection. We identified somatic hypermutations that were recurrently selected in such public clonotypes, indicating that affinity maturation occurs in mouse PP GCs under homeostatic conditions. Thus, persistent gut antigens select recurrent BCR clonotypes to seed chronic PP GC responses.

Citation

Huan Chen, Yuxiang Zhang, Adam Yongxin Ye, Zhou Du, Mo Xu, Cheng-Sheng Lee, Joyce K Hwang, Nia Kyritsis, Zhaoqing Ba, Donna Neuberg, Dan R Littman, Frederick W Alt. BCR selection and affinity maturation in Peyer's patch germinal centres. Nature. 2020 Jun;582(7812):421-425