Abstract
The adaptive immune system uses several strategies to generate a repertoire of T cell receptors (TCR) with sufficient diversity to recognize the universe of potential pathogens. However, it remains unclear how differences in the T cell receptor (TCR) contribute to heterogeneity in T cell state. In this study, we used polychromatic flow cytometry to isolate highly pure CD4+/CD8+ naive and memory T cells, and applied deep sequencing to characterize corresponding TCR β-chain (TCRβ) complementary-determining region 3 (CDR3) repertoires. We find that shorter TCRβ CDR3s with fewer insertions were highly enriched during thymic selection. Antigen-experienced T cells (memory T cells) harbor shorter CDR3s vs. naive T cells. Moreover, the public TCRβ CDR3 clonotypes within cell subsets or interindividual tend to have shorter CDR3 length and a significantly larger size compared with “private” clonotypes. Taken together, shorter CDR3s highly enriched during thymic selection and antigen-driven selection, and further enriched in public T-cell responses. These results indicated that it may be evolutionary pressures drive short CDR3s to recognize most of antigen in nature.
Highlights
To ward off a wide variety of pathogens, the human adaptive immune system harbors a vast array of T cell receptors (TCR), collectively referred to as the Tcell receptors (TCRs)-repertoire
We used generation sequencing technology to investigate the TCR β-chain (TCRβ) complementary-determining region 3 (CDR3) repertoires of different T cell subsets (CD4+CD45RA+, 4RA; CD4+CD45RO+, 4RO; CD8+CD45RA+, 8RA; and CD8+CD45RO+, 8RO) that had been purified from normal human peripheral blood samples
We found that CDR3 length distributions differed between the naive and memory TCRβ repertoires, which showed a shift toward shorter clonotypes in memory cells vs. naive, no matter at the CD4+ cell level (Figure 3A) or CD8+ cell level (Figure 3B)
Summary
To ward off a wide variety of pathogens, the human adaptive immune system harbors a vast array of TCRs, collectively referred to as the TCR-repertoire. The genes that encode the two primary types of TCRs, αβ, and γδ. The TCR β-chain is comprised of a variable (termed TRBV), diversity (TRBD), joining (TRBJ), and constant region (TRBC). The potential TCRβ repertoire consists of over 50 TRBV genes, two TRBD genes, 13 TRBJ genes, and two TRBC genes. In course of T-cell maturation, TCR locus recombination events can produce non-functional TCRs with frameshifts or stop codons [3]. In this case, the T cell tries to arrange the second allele, and if the successful (in-frame) TCR formation occurs, the T cell carries both functional and non-functional TCR sequences [2, 4].
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