Abstract
The diversity of T-cell receptor (TCR) repertoires, as generated by somatic DNA rearrangements, is central to immune system function. High-throughput sequencing technologies now allow examination of antigen receptor repertoires at single-nucleotide and, more recently, single-cell resolution. The TCR repertoire can be altered in the context of infections, malignancies or immunological disorders. Here we examined the diversity of TCR clonality and its association with pathogenesis and prognosis in adult T-cell leukemia/lymphoma (ATL), a malignancy caused by infection with human T-cell leukemia virus type-1 (HTLV-1). We analyzed 62 sets of high-throughput RNA sequencing data from 59 samples of HTLV-1−infected individuals—asymptomatic carriers (ACs), smoldering, chronic, acute and lymphoma ATL subtypes—and three uninfected controls to evaluate TCR distribution. Based on these TCR profiles, CD4-positive cells and ACs showed polyclonal patterns, whereas ATL patients showed oligo- or monoclonal patterns (with 446 average clonotypes across samples). Expression of TCRα and TCRβ genes in the dominant clone differed among the samples. ACs, CD4-positive samples and smoldering patients showed significantly higher TCR diversity compared with chronic, acute and lymphoma subtypes. CDR3 sequence length distribution, amino acid conservation and gene usage variability for ATL patients resembled those of peripheral blood cells from ACs and healthy donors. Thus, determining monoclonal architecture and clonal diversity by RNA sequencing might be useful for prognostic purposes and for personalizing ATL diagnosis and assessment of treatments.
Highlights
The T-cell receptor (TCR), which is generated through random rearrangement of genomic V(D)J—variable(diversity)joining—segments, is the mediator of specific antigen recognition by T lymphocytes.[1,2] This process is directly analogous to the generation of antibody diversity by somatic VDJ recombination of the Bcell receptor locus in B lymphocytes.[3]
Our study presents a detailed view of the TCR repertoire among 56 individuals with different subtypes of adult T-cell leukemia/lymphoma (ATL), three asymptomatic carriers (ACs) and three healthy donors (CD4-positive cells)
As we move toward an era of personalized medicine for ATL and other malignancies, there is an increasing demand for simple, quantitative and reproducible measures enabling the characterization and tracking of cancer cells and their associated microenvironment
Summary
The T-cell receptor (TCR), which is generated through random rearrangement of genomic V(D)J—variable(diversity)joining—segments, is the mediator of specific antigen recognition by T lymphocytes.[1,2] This process is directly analogous to the generation of antibody diversity by somatic VDJ recombination of the Bcell receptor locus in B lymphocytes.[3] The TCR consists of a heterodimer of two chains (αβ or γδ), both of which are products of V(D)J recombination.[4,5] An individual’s TCR repertoire is shaped by biases during the process of VDJ recombination and by the subsequent expansion and deletion of certain T-cell clones upon antigen recognition during T-cell development in the thymus and later in the periphery.[3,6] Because this somatic rearrangement occurs only in the T-cell genome and produces an extremely diverse repertoire of TCRs as a hallmark of the cellular adaptive immune system, it can be effectively used as a unique tag to enumerate and quantify T-cell clonality.[7,8] The vast majority of TCR variation is within complementarity-determining region 3 (CDR3), which encompasses the VDJ recombination junctions and encodes the portion of the TCR that directly contacts peptidebound major histocompatibility complex molecules.[1,9] the sequence of CDR3 and the identity of the flanking V and J gene segments are widely used to classify TCR variants.[7]
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