This week we profile a recent publication in eLife from the laboratory of
Dr. Philip Bradley (pictured) at the Fred Hutchinson Cancer Research Center.
What background information would someone who is completely unfamiliar with your field need to know to understand the findings in your paper?
Our immune systems protect us from infectious agents such as bacteria and viruses. The adaptive arm of the immune system builds up a memory of past infections in order to respond more quickly in future encounters. This memory is stored in the form of subpopulations of T and B cells with receptors on their surfaces that recognize pathogens. T cells recognize pathogen-derived peptide fragments presented on the surface of infected cells by carrier proteins. In humans, the genes encoding these carrier proteins (termed the human leukocyte antigen or HLA system) are among the most variable in the genome; this diversity provides enhanced protection from pathogens since different HLA alleles present different pathogen-derived peptides for surveillance by T cells, making it harder for pathogens to escape detection by acquiring mutations.
What exact research question did you set out to answer and why?
High-throughput DNA sequencing has enabled deep profiling of the set of receptors that T and B cells use to recognize infections, which opens a potential route to the detection of past and present infectious disease exposures and even cancer (whose presence is also monitored by the adaptive immune system). We set out to discover signatures of immune exposure and genetic variation in T cell receptor (TCR) sequencing data for a large cohort of healthy human subjects.
What are the most important findings of your paper?
We discovered clusters of TCR sequences that occur together across subjects in the cohort and may be indicative of shared immune exposures in the subjects they occur in. We performed a quantitative analysis of population-level relationships between individual HLA alleles and TCR sequences. We uncovered a striking imprint of common pathogens such as influenza, cytomegalovirus, and Epstein-Barr virus on the shared TCR repertoire. Finally, guided by three-dimensional structures of TCR engaging with peptide presented by HLA, we identified how variation at specific HLA sequence positions determines the diversity of TCR sequences that can recognize the HLA.
Who might eventually benefit from the findings of your study, and what would need to be done before we could achieve these benefits?
A better understanding of the T cell receptor repertoire could aid in diagnosing and treating infectious and autoimmune diseases. Given the recent success of cancer immunotherapy, it is plausible that better methods for identifying tumor-derived epitopes and/or the T cell receptors targeting them could enhance cancer treatment. These advances will depend on follow-up studies to characterize the T cell repertoire features identified in our study, some of which are underway in our labs.