I apologize but I am still trying to get up to date on the immunology field. All the papers I read are solely focusing on the beta chain of TCRs. Why is this the case? Shouldn't efforts be focused on both the beta and alpha? As the receptor is made up of both...
Dear Matt Kubit,
It is a basic but important question to improve our understanding on TCR.
TCR alpha chain rearrangement occurs in cells (in thymocyte) that undergone TCRB chain rearrangement. Immunologically, a cell with similar or same TCR beta chain and different or distinct TCR alpha chain can be isolated from an single individual. Whereas, a cell with different TCR B chain and same TCR alpha chain was not observed from a single individual. Hence, the amount of functional repertoires maintained within a single individual may directly related with TCR B chain.
At the same time, it is hypothesized that TCR alpha chain posses greater diversity than TCR Beta chain which is evident from the information that TCR alpha chain has more contacts on peptide. In short, foreign antigen or peptide recognition majorly depends on TCR alpha chain. It also suggest us that the repertoire of TCR is related with TCR alpha chain. Now which is more important?
Of note, TCR alpha chain rearrangement occurs on cells selected with TCR B chain only. Let us assume that you have a book shelf (TCR A Chain) and several books (TCR B chain). We need to have atleast one book ( TCR B chain) to keep in the bookshelf (TCR alpha chain). But, we have roughly 1015 books (TCR and B chain repertoire) in our system. Here we need a system to define, locate and relocate the books at the earliest without confusions. Existing evidences indicated that TCR beta selection is the critical step for development and maintenance of immunological repertoire in a single individual. In simpler words, cells with productive TCR B chains only selected for further expansion and maturation. Thus, TCR beta chain attracted much more interest in the relevant researches.
What is the use of too much TCR beta chain diversity without TCR alpha chain diversity? Hence, it is not wise not to limit our understanding (especially immunological reactions) based on certain facts.
Most studies have focused on TCR beta sequencing but to understand the specificity of a T-cell receptor, especially for functional/therapeutic implications, more research is being dedicated to characterizing both chains of the receptor. An example is in the paper by Tran et al in NEJM regarding targeting the KRAS G12D mutation. In the supplementary data (page 18 in the link below) you can see that both chains were sequenced. They detected an alpha chain that was shared among two T-cell clones targeting the same mutation in two different patients; this underscores the importance of sequencing the alpha chain as well.
https://www.nejm.org/doi/suppl/10.1056/NEJMoa1609279/suppl_file/nejmoa1609279_appendix.pdf
Hope this is helpful!
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