Longitudinal immunosequencing in healthy people reveals persistent T cell receptors rich in highly public receptors

Abstract

Background The adaptive immune system maintains a diversity of T cells capable of recognizing a broad array of antigens. Each T cell’s specificity for antigens is determined by its T cell receptors (TCRs), which together across all T cells form a repertoire of millions of unique receptors in each individual. Although many studies have examined how TCR repertoires change in response to disease or drugs, few have explored the temporal dynamics of the TCR repertoire in healthy individuals. Results Here we report immunosequencing of TCR β chains (TCRβ) from the blood of three healthy individuals at eight time points over one year. TCRβ repertoires of all peripheral-blood T cells and sorted memory T cells clustered clearly by individual, systematically demonstrating that TCRβ repertoires are specific to individuals across time. This individuality was absent from TCRβs from naive T cells, suggesting that the differences resulted from an individual’s antigen exposure history, not genetic background. Many characteristics of the TCRβ repertoire (e.g., diversity, clonality) were stable across time, although we found evidence of T cell expansion dynamics even within healthy individuals. We further identified a subset of “persistent” TCRβs present across all time points. These receptors were rich in clonal and highly public receptors and may play a key role in immune system maintenance. Conclusions Our results highlight the importance of longitudinal sampling of the immune system, providing a much-needed baseline for TCRβ dynamics in healthy individuals. Such a baseline will improve interpretation of changes in the TCRβ repertoire during disease or treatment. Electronic supplementary material The online version of this article (10.1186/s12865-019-0300-5) contains supplementary material, which is available to authorized users.

Comprehensive analysis of antiviral adaptive immunity formation and reactivation down to single-cell level

“…Most previous studies focused on TCR beta repertoires, partially because the diversity of TCR beta is higher, making it a better marker for clonal tracking [39]. We found that TCR alpha may be used for clonal track-ing as well, giving almost the same results as TCR beta in terms of the number of expanding clonotypes and their cumulative fractions on different timepoints.…”

Inferring the immune response from repertoire sequencing

“…The proposed framework is not limited to identifying a response during an acute infection, but can also be used as method for learning the dynamics from time dependent data even in the absence of an external stimulus [19]. Here we specifically assumed expansion dynamics with strong selection.…”

“…This approach has demonstrated the potential to identify particular receptors involved in the immune response, offering an alternative to in vitro binding or functional assays [15,16] or to RepSeq studies of cohorts with a common condition [17]. The natural temporal evolution of TCR repertoires has also been studied as a function of age across healthy individuals [18] or across time in single healthy individuals [19]. While these experiments yield a wealth of data, it is not always clear how to process and analyse them, or to link them to existing models of lymphocyte dynamics and proliferation [20][21][22][23].…”

Pegylated recombinant human granulocyte colony‐stimulating factor regulates the immune status of patients with small cell lung cancer

“…The distribution of peripheral lymphocyte subsets reflects the immune status and is correlated with survival in SCLC . Further, the specificity of each T cell for antigens is determined by its T‐cell receptors (TCRs), which together across all T cells form a repertoire of millions of unique receptors in each individual . TCR diversity is predominantly derived from the highly variable complementarity‐determining region 3 (CDR3) and is generated by random rearrangement and junction region mutation of the V‐D‐J regions, which are three fragments located in TCR‐coding genes.…”

“…13 Further, the specificity of each T cell for antigens is determined by its T-cell receptors (TCRs), which together across all T cells form a repertoire of millions of unique receptors in each individual. 14 TCR diversity is predominantly derived from the highly variable complementaritydetermining region 3 (CDR3) and is generated by random rearrangement and junction region mutation of the V-D-J regions, which are three fragments located in TCR-coding genes. Many studies have shown that lymphocytes recognize the patient's unique mutations in the peripheral blood 15,16 ; TCR repertoire in peripheral blood could be a biomarker of clinical outcomes for chemotherapy and immunotherapy.…”