NKT and MAIT invariant TCRα sequences can be produced efficiently by VJ gene recombination

Greenaway, Hui Yee; Ng, Benedict; Price, David A.; Douek, Daniel C.; Davenport, Miles P.; Venturi, Vanessa

doi:10.1016/j.imbio.2012.04.003

Cited by 61 publications

(73 citation statements)

References 80 publications

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“…This finding is in agreement with the observation made for the out-of-frame (generated) repertoire by Murugan et al (2). (32,33). Indeed, we found all of the CDR3 sequences originated from MAIT cells and 8 of 12 CDR3 sequences originated from NKT cells (32) in our datasets.…”

Section: Discussionsupporting

confidence: 93%

Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

Zvyagin

Pogorelyy

Ivanova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

118

149

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Adaptive immunity in humans is provided by hypervariable Ig-like molecules on the surface of B and T cells. The final set of these molecules in each organism is formed under the influence of two forces: individual genetic traits and the environment, which includes the diverse spectra of alien and self-antigens. Here we assess the impact of individual genetic factors on the formation of the adaptive immunity by analyzing the T-cell receptor (TCR) repertoires of three pairs of monozygous twins by next-generation sequencing. Surprisingly, we found that an overlap between the TCR repertoires of monozygous twins is similar to an overlap between the TCR repertoires of nonrelated individuals. However, the number of identical complementary determining region 3 sequences in two individuals is significantly increased for twin pairs in the fraction of highly abundant TCR molecules, which is enriched by the antigen-experienced T cells. We found that the initial recruitment of particular TCR V genes for recombination and subsequent selection in the thymus is strictly determined by individual genetic factors. J genes of TCRs are selected randomly for recombination; however, the subsequent selection in the thymus gives preference to some α but not β J segments. These findings provide a deeper insight into the mechanism of TCR repertoire generation.immunogenetics | TCR repertoire analysis | twin studies

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Section: Discussionsupporting

confidence: 93%

Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

Zvyagin

Pogorelyy

Ivanova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

118

149

View full text Add to dashboard Cite

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“…In humans, some variation in the composition of the junction exists, suggesting a selective pressure operating at the protein level 14 . Nevertheless, a recent computer simulation of gene recombination events proposed that the invariant TCRa chains of MAIT and NKT cells can be generated by a recombination process involving various convergent mechanisms 20 .…”

mentioning

confidence: 99%

Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire

et al. 2014

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Mucosal-associated invariant T (MAIT) cells are abundant in humans and recognize conserved bacterial antigens derived from riboflavin precursors, presented by the nonpolymorphic MHC class I-like molecule MR1. Here we show that human MAIT cells are remarkably oligoclonal in both the blood and liver, display high inter-individual homology and exhibit a restricted length CDR3b domain of the TCRVb chain. We extend this analysis to a second sub-population of MAIT cells expressing a semi-invariant TCR conserved between individuals. Similar to 'conventional' MAIT cells, these lymphocytes react to riboflavin-synthesizing microbes in an MR1-restricted manner and infiltrate solid tissues. Both MAIT cell types release Th0, Th1 and Th2 cytokines, and sCD40L in response to bacterial infection, show cytotoxic capacity against infected cells and promote killing of intracellular bacteria, thus suggesting important protective and immunoregulatory functions of these lymphocytes.

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“…Recent studies provided evidence that MAIT and NKT cells have a close lineage relationship and are highly susceptible to apoptosis, a feature not shared with conventional T cells (21,22,41). We next investigated the numerical and functional relationships between MAIT cells and NKT cells.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous studies and those by other groups have demonstrated numerical and functional deficiencies of NKT cells in autoimmune diseases (17)(18)(19)(20). Although MAIT and NKT cells exclusively share the expression of the transcription factor PZLF (ZBTB16), emphasizing a close lineage relationship between these two distinct subsets, MAIT cell ontogeny is clearly different from NKT cells (5,21,22).…”

mentioning

confidence: 82%

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

Cho

Kee

Kim

et al. 2014

The Journal of Immunology

155

163

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Mucosal-associated invariant T (MAIT) cells contribute to protection against certain microorganism infections and play an important role in mucosal immunity. However, the role of MAIT cells remains enigmatic in autoimmune diseases. In this study, we examined the level and function of MAIT cells in patients with rheumatic diseases. MAIT cell, cytokine, and programmed death-1 (PD-1) levels were measured by flow cytometry. Circulating MAIT cell levels were significantly reduced in systemic lupus erythematosus (SLE) and rheumatoid arthritis patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets, and significantly correlated with disease activity, such as SLE disease activity index and 28-joint disease activity score. Interestingly, MAIT cell frequency was significantly correlated with NKT cell frequency in SLE patients. IFN-γ production in MAIT cells was impaired in SLE patients, which was due to an intrinsic defect in the Ca2+/calcineurin/NFAT1 signaling pathway. In SLE patients, MAIT cells were poorly activated by α-galactosylceramide–stimulated NKT cells, thereby showing the dysfunction between MAIT cells and NKT cells. Notably, an elevated expression of PD-1 in MAIT cells and NKT cells was associated with SLE. In rheumatoid arthritis patients, MAIT cell levels were significantly higher in synovial fluid than in peripheral blood. Our study primarily demonstrates that MAIT cells are numerically and functionally deficient in SLE. In addition, we report a novel finding that this MAIT cell deficiency is associated with NKT cell deficiency and elevated PD-1 expression. These abnormalities possibly contribute to dysregulated mucosal immunity in SLE.

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NKT and MAIT invariant TCRα sequences can be produced efficiently by VJ gene recombination

Cited by 61 publications

References 80 publications

Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

Parallel T-cell cloning and deep sequencing of human MAIT cells reveal stable oligoclonal TCRβ repertoire

Mucosal-Associated Invariant T Cell Deficiency in Systemic Lupus Erythematosus

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