Activation Induced Cytidine Deaminase and the Evolution of Antigen Receptor Immunogenetics
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AbstractAll jawed vertebrates share fundamental components of the adaptive immune system. Cartilaginous fish are the most divergent jawed vertebrate group relative to mammals and use a major histocompatibility complex, B cells, and T cells. RAG mediates the rearrangement of gene segments to create both B and T cell receptors. B cell receptors further undergo diversification after antigen exposure when activated B cells extensively alter their rearranged genes to enhance affinity to antigen. This receptor modification is mediated by the enzyme activation-induced cytidine deaminase (AID). Remarkably, AID also catalyzes receptor modifications in alpha chain of TCR within shark thymus. Thus, the ancestor to modern vertebrates may have used an AID-like enzyme for lymphocyte receptor development, a mechanism lost in later vertebrates because of its potential for breaking down self-tolerance in mature lymphocytes. At the other end of the vertebrate tree, the repertoire of Bos taurus antibodies is characterized by a subset of heavy chains with variable domains VH encoding ultralong complementarity determining region CDR3. These ultralong CDR3 range from forty to over seventy amino acids in length and form a unique beta-ribbon stalk and disulfide bonded knob. Deep sequence analysis of the B. taurus heavy chain repertoire unveiled ultralong CDR3s were products of rearrangement between the longest VH and DH segments, IGHV1-1 and DH8. Both germline and somatic genetic factors and processes appear to be involved in diversification of this structurally unusual bovine ultralong CDR3 repertoire. These unheralded uses of AID will be discussed in the broader context of immunogenetics evolution.
