Zuo Teng, Gautam Avneesh, Saghaei Shahab, Khobragade Sweta N, Ahmed Rahaman, Mahdavinia Azadeh, Zarghami Mehrdad, Pacheco Gaspar A, Green Kenneth, Travers Meghan, Garcia Nicholas, Allahyari Zahra, Rao Vishal, Kumar Sachin, Novak Robert, Hwang Joyce K, Wesemann Duane R
Department of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Department of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Immunity. 2025 Jun 10;58(6):1396-1410.e7. doi: 10.1016/j.immuni.2025.04.014. Epub 2025 May 7.
B cell somatic hypermutation (SHM) and selection in germinal centers (GCs) enhance antibody affinity for antigen. Here, we investigated whether SHM-based antibody evolution is restricted to specificities established through V(D)J recombination in the primary repertoire. Tracking pre-defined non-specific B cells across multiple immunization models revealed that non-cognate B cells within GCs undergo SHM. Under conditions of limited B cell competition, these B cells generated de novo antigen recognition to multiple epitopes across diverse model antigens. Phylogenetic analyses identified diverse mutational pathways leading to new antigen affinities, and enhanced T cell co-stimulation further promoted new antigen recognition. Our data support a model in which B cell competition-rather than an intrinsic requirement for specific affinity-limits the emergence of new affinities through SHM, highlighting the mammalian adaptive immune system's ability to explore antibody-antigen interactions beyond those encoded by the V(D)J-dependent primary repertoire, demonstrating the flexibility of SHM in not only ripening but also reshaping specificity.
B细胞体细胞超突变（SHM）以及生发中心（GC）中的选择过程可增强抗体对抗原的亲和力。在此，我们研究了基于SHM的抗体进化是否局限于通过初级库中V（D）J重组所确立的特异性。在多种免疫模型中追踪预先定义的非特异性B细胞，结果显示GC内的非同源B细胞会发生SHM。在B细胞竞争有限的条件下，这些B细胞对多种模型抗原的多个表位产生了全新的抗原识别能力。系统发育分析确定了导致新抗原亲和力的多种突变途径，而增强的T细胞共刺激进一步促进了新抗原识别。我们的数据支持这样一种模型，即B细胞竞争而非对特定亲和力的内在需求，通过SHM限制了新亲和力的出现，这突出了哺乳动物适应性免疫系统探索超出V（D）J依赖性初级库所编码的抗体-抗原相互作用的能力，证明了SHM不仅在成熟而且在重塑特异性方面的灵活性。
