Expression of Immunoglobulin Receptors with Distinctive Features Indicating Antigen Selection by Marginal Zone B Cells from Human Spleen
Marginal zone (MZ) B cells, identified as surface (s)IgMhighsIgDlowCD23low/−CD21+CD38− B cells, were purified from human spleens, and the features of their V(D)J gene rearrangements were investigated and compared with those of germinal center (GC), follicular mantle (FM) and switched memory (SM) B cells. Most MZ B cells were CD27+ and exhibited somatic hypermutations (SHM), although to a lower extent than SM B cells. Moreover, among MZ B-cell rearrangements, recurrent sequences were observed, some of which displayed intraclonal diversification. The same diversifying sequences were detected in very low numbers in GC and FM B cells and only when a highly sensitive, gene-specific polymerase chain reaction was used. This result indicates that MZ B cells could expand and diversify in situ and also suggested the presence of a number of activation-induced cytidine deaminase (AID)-expressing B cells in the MZ. The notion of antigen-driven expansion/selection in situ is further supported by the VH CDR3 features of MZ B cells with highly conserved amino acids at specific positions and by the finding of shared (“stereotyped”) sequences in two different spleens. Collectively, the data are consistent with the notion that MZ B cells are a special subset selected by in situ antigenic stimuli.
Grant support was provided by the Italian Association for Cancer Research (AIRC) “Special Program Molecular Clinical Oncology-5 per mille,” number 9980, 2010/15 (to M Colombo); by Compagnia di San Paolo 4824 SD/CV, 2007.2880 (to F Fais and G Cutrona); and by Cariplo Foundation, Milan, Italy (to K Stamatopoulos) and the ENosAI project (code 09SYN-13-880), cofunded by the European Union and the Hellenic General Secretariat for Research and Technology (to K Stamatopoulos).
The authors would like to thank Nicholas Chiorazzi for revising the manuscript. Special thanks go to Laura Veroni for excellent secretarial support.
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