BCR is the New Antibody, TCR is still a T Cell Receptor

Posted from Discovering Biology in a Digital World by Todd Smith on Tue Jul 10, 2018

Scientists, and science editors love acronyms. While they can be  obfuscating, they help reduce cumbersome language. 

For many years the term antibody was commonly abbreviated as Ab (Ig and others too). As high-throughput DNA sequencing has become a standard way to measure antibody and T cell receptor profiles it has also become common to compare these receptors together in publications.  T cell receptors are abbreviated as TCRs, but comparing an Ab (or Ig) to a TCR does not have a nice parallelism. Hence, BCR (for B Cell Receptor) was born with IRs (immune receptors) being a way to collectively describe BCRs and TCRs.

Similarities and Differences between BCRs and TCRs

BCRs and TCRs are the recognition molecules of our immune system; the molecules they bind are called antigens. Once an IR binds an antigen, its structural elements and local context are used to distinguish self molecules from foreign molecules that indicate infection or disease. BCRs and TCRs are similar in many ways, but their differences form the core of how self and non-self are recognized.   

As previously discussed, Digital World Biology is designing an immuno-bioinformatics class for Shoreline Community College. An underlying goal of the course is learn how high-throughput data collection methods and bioinformatics are used to uncover the underlying biology of the immune system. To understand the bioinformatics methods that are used, we need to understand the similarities and differences between BCRs and TCRs. These similarities and differences can be grouped by structure, diversity, and antigens. 

Structure - BCRs and TCRs have common structural features that include multiple protein chains and protein domains within each chain that are made up of beta sheets. At the “tips” of each structure are the variable regions that recognize antigens. The protein chains that form BCRs or TCRs are encoded by separate genetic loci that undergo recombination as immune cells develop. 

From this general structure BCRs and TCRs diverge. TCRs are dimers of two protein chains: alpha (α) and beta (β), with a small percent formed by gamma (γ) and delta (δ) chains. In humans and many other animals BCRs are dimers of heavy and light chain dimers, four protein chains in all. Unlike TCRs which are either α/β or γ/δ dimers, BCR light chain proteins are encoded by the kappa (κ) and lambda (λ) genetic loci. The final BCR will have either κ or λ chains; they are not mixed. 

Diversity - Immune receptors can recognize a nearly infinite number of molecules. Receptor diversity is generated through genetic recombination. The BCR and TCR loci contain a large number of small genes referred to as variable (V), diversity (D), and joining (J) genes. BCR heavy chains are encoded by different combinations of V, D, and J genes, and BCR light chain loci have only V and J genes. TCRs are similar in that one chain (α) has only V, J genes and the other (β) has V, D, and J genes. 

Each receptor type is encoded by combinations of 100s of V, D, or J genes. When all of the combinations are considered, the total number of possible receptors is several million. This number is greatly increased through "sloppy" joining. During V-D-J, or V-J recombination, additional nucleotides are inserted or deleted at the junction sites to create a nearly infinite number of possibilities. Because the junction sites are the most diverse they serve as the CDRs (complementary determining regions) of the receptor molecules. 

From a diversity perspective BCRs and TCRs are very similar with a few significant exceptions, BCRs have increased functional diversity through their constant region (C-region) genes. There are five classes of C-regions (α, δ, ε, γ, μ), and a BCR is defined by its constant region (IgA, IgD, IgE, IgG, and IgM). The C-region determines what happens after the antibody binds and antigen. As an immune response evolves, a BCR can change its C-region (class switching) to alter its functional role.

C-regions and class switching leads to another important difference between BCRs and TCRs. TCRs are always bound to cells whereas BCRs can be either membrane bound or free in solution. The BCR constant region plus alternative splicing of domains within the C-region determine a BCR’s membrane bound or free state. 

Finally, BCRs can be “tuned” in that their ability to bind an antigen can improve overtime through a process called somatic hypermutation (SHM).

Antigens - The major structural differences between BCRs and TCRs reflect on the kinds of antigens they recognize and functions that they perform. 

BCRs’ different states between soluble and membrane bound allows these receptors to encounter antigens in different environments. They bind both soluble antigens and antigens bound to cells. The part of the antigen that is bound is called an epitope. In proteins, epitopes can be a linear sequence or be discontinuous. Discontinuous epitopes are formed from separate regions of a protein that come together as a protein folds into its three dimensional structure. 

TCRs, on the other hand, bind only linear epitopes. And, these epitopes must also be bound to one of two classes of MHC (Major Histocompatibility Complex) proteins. More on that later. 

Reference:

Numbers of V, D, J genes: http://www.imgt.org/IMGTrepertoire/LocusGenes/genetable/human/geneNumber...  

Acknowledgment of Support:  This material is based in part on work supported by the National Science Foundation under Grant Number DUE 1700441. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.