Dataset Information

Surface NKG2C Identifies Differentiated ??T-Cell Clones Expanded in Peripheral Blood.

ABSTRACT: T cells that express CD56 in peripheral blood of healthy humans represent a heterogeneous and poorly studied subset. In this work, we analyzed this subset for NKG2C expression. In both CD56⁺ and CD56^- subsets most of the NKG2C⁺ T cells had a phenotype of highly differentiated CD8⁺ TEMRA cells. The CD56⁺NKG2C⁺ T cells also expressed a number of NK cell receptors, such as NKG2D, CD16, KIR2DL2/DL3, and maturation marker CD57 more often than the CD56^-NKG2C⁺CD3⁺ cells. TCR ?-chain repertoire of the CD3⁺CD56⁺NKG2C⁺ cell fraction was limited by the prevalence of one or several clonotypes which can be found within the most abundant clonotypes in total or CD8⁺ T cell fraction TCR? repertoire. Thus, NKG2C expression in highly differentiated CD56⁺ T cells was associated with the most expanded ?? T cell clones. NKG2C⁺ T cells produced almost no IFN-? in response to stimulation with HCMV pp65-derived peptides. This may be partially due to the high content of CD45RA⁺CD57⁺ cells in the fraction. CD3⁺NKG2C⁺ cells showed signs of activation, and the frequency of this T-cell subset in HCMV-positive individuals was positively correlated with the frequency of NKG2C⁺ NK cells that may imply a coordinated in a certain extent development of the NKG2C⁺ T and NK cell subsets under HCMV infection.

SUBMITTER: Kovalenko EI

PROVIDER: S-EPMC7921799 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Surface NKG2C Identifies Differentiated αβT-Cell Clones Expanded in Peripheral Blood.

Kovalenko Elena I EI Zvyagin Ivan V IV Streltsova Maria A MA Mikelov Artem I AI Erokhina Sofya A SA Telford William G WG Sapozhnikov Alexander M AM Lebedev Yury B YB

Frontiers in immunology 20210216

T cells that express CD56 in peripheral blood of healthy humans represent a heterogeneous and poorly studied subset. In this work, we analyzed this subset for NKG2C expression. In both CD56+ and CD56- subsets most of the NKG2C+ T cells had a phenotype of highly differentiated CD8+ TEMRA cells. The CD56+NKG2C+ T cells also expressed a number of NK cell receptors, such as NKG2D, CD16, KIR2DL2/DL3, and maturation marker CD57 more oft ...[more]

PMID: 33664730

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Project description:IntroductionB cells are acknowledged as crucial players in the pathogenesis of multiple sclerosis (MS). Several disease modifying drugs including cladribine have been shown to exert differential effects on peripheral blood B cell subsets. However, little is known regarding functional changes within the peripheral B cell populations. In this study, we obtained a detailed picture of B cell repertoire changes under cladribine treatment on a combined immunoglobulin (Ig) transcriptome and proteome level.MethodsWe performed next-generation sequencing of Ig heavy chain (IGH) transcripts and Ig mass spectrometry in cladribine-treated patients with relapsing-remitting multiple sclerosis (n = 8) at baseline and after 6 and 12 months of treatment in order to generate Ig transcriptome and Ig peptide libraries. Ig peptides were overlapped with the corresponding IGH transcriptome in order to analyze B cell clones on a combined transcriptome and proteome level.ResultsThe analysis of peripheral blood B cell percentages pointed towards a significant decrease of memory B cells and an increase of naive B cells following cladribine therapy. While basic IGH repertoire parameters (e.g. variable heavy chain family usage and Ig subclasses) were only slightly affected by cladribine treatment, a significantly decreased number of clones and significantly lower diversity in the memory subset was noticeable at 6 months following treatment which was sustained at 12 months. When looking at B-cell clones comprising sequences from the different time-points, clones spanning between all three time-points were significantly more frequent than clones including sequences from two time-points. Furthermore, Ig proteome analyses showed that Ig transcriptome specific peptides could mostly be equally aligned to all three time-points pointing towards a proportion of B-cell clones that are maintained during treatment.DiscussionOur findings suggest that peripheral B cell related treatment effects of cladribine tablets might be exerted through a reduction of possibly disease relevant clones in the memory B cell subset without disrupting the overall clonal composition of B cells. Our results -at least partially- might explain the relatively mild side effects regarding infections and the sustained immune response after vaccinations during treatment. However, exact disease driving B cell subsets and their effects remain unknown and should be addressed in future studies.

Project description:Clonal diversity in multiple myeloma (MM) includes both MM-related and MM-unrelated clonal expansions which are subject to dominance exerted by the MM clone. Here we show evidence for the existence of minor but highly expanded unrelated B-cell clones in patients with MM defined by their complementary determining region 3 (CDR3) peak. We further characterize these clones over the disease and subsequent treatment. Second clones were identified by their specific IgH-VDJ sequences that are distinct from those of dominant MM clones. Clonal frequencies were determined through semi-quantitative PCR, quantitative PCR and single-cell polymerase chain reaction of the clone-specific sequence. In 13/74 MM patients, more than one dominant CDR3 peak was identified with 12 patients (16%) being truly biclonal. Second clones had different frequencies, were found in different locations and were found in different cell types from the dominant MM clone. Where analysis was possible, they were shown to have chromosomal characteristic distinct from those of the MM clone. The frequency of the second clone also changed over the course of the disease and often persisted despite treatment. Molecularly-defined second clones are infrequent in monoclonal gammopathy of undetermined significance (MGUS, 1/43 individuals or 2%), suggesting that they may arise at relatively late stages of myelomagenesis. In further support of our findings, biclonal gammopathy and concomitant MM and CLL (chronic lymphocytic leukemia) were confirmed to originate from two unrelated clones. Our data supports the idea that the clone giving rise to symptomatic myeloma exerts clonal dominance to prevent expansion of other clones. MM and second clones may arise from an underlying niche permissive of clonal expansion. The clinical significance of these highly expanded but unrelated clones remains to be confirmed. Overall, our findings add new dimensions to evaluating related and unrelated clonal expansions in MM and the impact of disease evolution and treatment on clonal diversity.

Dataset Information

Surface NKG2C Identifies Differentiated ??T-Cell Clones Expanded in Peripheral Blood.

Publications

Surface NKG2C Identifies Differentiated αβT-Cell Clones Expanded in Peripheral Blood.

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