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Preliminary analysis of spatial-temporal homogeneity and heterogeneity of TCR ? chain CDR3 repertoires in BALB/c mice.

ABSTRACT: The T-cell response and tolerance in non-lymph tissues differs from those in lymph tissues such as the spleen and thymus. The distribution and composition of the TCR repertoires in non-lymph tissues and how they differ and associate with their counterparts in lymph tissue remain unclear. Thus, we studied the thymus, spleen, blood, liver and small intestine of BALB/c mice at the ages of one, three and five months to carry out a preliminary analysis of the spatial-temporal homogeneity and heterogeneity of the total TCR ? chain CDR3 repertoire using high-throughput sequencing technology and immune bioinformatics approaches. The data show that the diversity of the CDR3 repertoires was decreased as the mouse age increased, except in the small intestine. The number of low-expanded clones in the CDR3 repertoires was greatest in the thymus, followed by the spleen, blood, liver and small intestine, and highly expanded clones had an opposite trend in the different mice ages. The thymus and the spleen showed the greatest overlap of CDR3 sequences with the other tissues across the different mice ages. The distribution of the CDR3 repertoire length was normal, with a median of 14 aa in all the mouse tissues, except the small intestine of the one-month-old mice had a median of 12 aa. In summary, the composition and characteristics of the CDR3 repertoires in the thymus were similar to those in the spleen, and repertoires in the blood were similar to those in the liver; only the small intestine showed a unique composition. These results offer a novel method to explore the source, differentiation, proliferation and response of distinct T cells in different tissues at different mice ages.

SUBMITTER: Li Y

PROVIDER: S-EPMC6420717 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Preliminary analysis of spatial-temporal homogeneity and heterogeneity of TCR β chain CDR3 repertoires in BALB/c mice.

Li Yuehong Y Ma Long L Dong Xiaoheng X Pan Yurong Y Shi Bin B He Xiaoyan X Zhang Teng T Sun Suhong S Yao Xinsheng X

International journal of molecular epidemiology and genetics 20190215 1

The T-cell response and tolerance in non-lymph tissues differs from those in lymph tissues such as the spleen and thymus. The distribution and composition of the TCR repertoires in non-lymph tissues and how they differ and associate with their counterparts in lymph tissue remain unclear. Thus, we studied the thymus, spleen, blood, liver and small intestine of BALB/c mice at the ages of one, three and five months to carry out a preliminary analysis of the spatial-temporal homogeneity and heteroge ...[more]

PMID: 30911358

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Project description:BackgroundCD4 T lymphocyte activation requires T cell receptor (TCR) engagement by peptide/MHC (major histocompatibility complex) (pMHC). The TCR complementarity-determining region 3 (CDR3) contains variable ? and ? loops critical for pMHC recognition. During any immune response, tuning of TCR usage through progressive clonal selection occurs. Th1 and Th2 cells operate at different avidities for activation and display distinct transcriptional programs, although polarization may be plastic, influenced by pathogens and cytokines. We therefore hypothesized that CDR3?? sequence features may intrinsically influence CD4 phenotype during progression of a response.ResultsWe show that CD4 polarization involves distinct CDR3? usage: Th1 and Th17 cells favored short TCR CDR3? sequences of 12 and 11 amino acids, respectively, while Th2 cells favored elongated CDR3? loops of 14 amino acids, with lower predicted affinity. The dominant Th2- and Th1-derived TCR? sequences with 14 amino acid CDR3 loops and 12 amino acid CDR3 loops, respectively, were expressed in TCR transgenics. The functional impact of these TCR? transgenes was assessed after in vivo priming with a peptide/adjuvant. The short, Th1-derived receptor transgenic T cell lines made IFN?, but not IL-4, 5 or 13, while the elongated, Th2-derived receptor transgenic T cell lines made little or no IFN?, but increased IL-4, 5 and 13 with progressive re-stimulations, mirrored by GATA-3 up-regulation. T cells from primed Th2 TCR? transgenics selected dominant TCR V? expansions, allowing us to generate TCR?? transgenics carrying the favored, Th2-derived receptor heterodimer. Primed T cells from TCR?? transgenics made little or no IL-17 or IFN?, but favored IL-9 after priming with Complete Freund's adjuvant and IL-4, 5, 9, 10 and 13 after priming with incomplete Freund's. In tetramer-binding studies, this transgenic receptor showed low binding avidity for pMHC and polarized T cell lines show TCR avidity for Th17 > Th1 > Th2. While transgenic expression of a Th2-derived, 'elongated' TCR-CDR3? and the TCR?? pair, clearly generated a program shifted away from Th1 immunity and with low binding avidity, cytokine-skewing could be over-ridden by altering peptide challenge dose.ConclusionWe propose that selection from responding clones with distinctive TCRs on the basis of functional avidity can direct a preference away from Th1 effector responses, favoring Th2 cytokines.

Dataset Information

Preliminary analysis of spatial-temporal homogeneity and heterogeneity of TCR ? chain CDR3 repertoires in BALB/c mice.

Publications

Preliminary analysis of spatial-temporal homogeneity and heterogeneity of TCR β chain CDR3 repertoires in BALB/c mice.

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