A divergent transcriptional landscape underpins the development and functional branching of MAIT cells

H. F. Koay, S. Su, D. Amann-Zalcenstein, S. R. Daley, I. Comerford, L. Miosge, C. E. Whyte, I. E. Konstantinov, Y. d'Udekem, T. Baldwin, P. F. Hickey, S. P. Berzins, J. Y.W. Mak, Y. Sontani, C. M. Roots, T. Sidwell, A. Kallies, Z. Chen, S. Nüssing, K. Kedzierska & 11 others L. K. Mackay, S. R. McColl, E. K. Deenick, D. P. Fairlie, J. McCluskey, C. C. Goodnow, M. E. Ritchie, G. T. Belz, S. H. Naik, D. G. Pellicci, D. I. Godfrey

Research output: Contribution to journalArticleResearchpeer-review

Abstract

MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 "mature" MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ-producing MAIT1 cells and interleukin-17-producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)-deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

Original languageEnglish
Article number6039
Number of pages16
JournalScience Immunology
Volume4
Issue number41
DOIs
Publication statusPublished - 22 Nov 2019

Cite this

Koay, H. F., Su, S., Amann-Zalcenstein, D., Daley, S. R., Comerford, I., Miosge, L., ... Godfrey, D. I. (2019). A divergent transcriptional landscape underpins the development and functional branching of MAIT cells. Science Immunology, 4(41), [6039]. https://doi.org/10.1126/sciimmunol.aay6039
Koay, H. F. ; Su, S. ; Amann-Zalcenstein, D. ; Daley, S. R. ; Comerford, I. ; Miosge, L. ; Whyte, C. E. ; Konstantinov, I. E. ; d'Udekem, Y. ; Baldwin, T. ; Hickey, P. F. ; Berzins, S. P. ; Mak, J. Y.W. ; Sontani, Y. ; Roots, C. M. ; Sidwell, T. ; Kallies, A. ; Chen, Z. ; Nüssing, S. ; Kedzierska, K. ; Mackay, L. K. ; McColl, S. R. ; Deenick, E. K. ; Fairlie, D. P. ; McCluskey, J. ; Goodnow, C. C. ; Ritchie, M. E. ; Belz, G. T. ; Naik, S. H. ; Pellicci, D. G. ; Godfrey, D. I. / A divergent transcriptional landscape underpins the development and functional branching of MAIT cells. In: Science Immunology. 2019 ; Vol. 4, No. 41.
@article{edc7499f2a98497ca6dddcdac69c9145,
title = "A divergent transcriptional landscape underpins the development and functional branching of MAIT cells",
abstract = "MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 {"}mature{"} MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ-producing MAIT1 cells and interleukin-17-producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)-deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.",
author = "Koay, {H. F.} and S. Su and D. Amann-Zalcenstein and Daley, {S. R.} and I. Comerford and L. Miosge and Whyte, {C. E.} and Konstantinov, {I. E.} and Y. d'Udekem and T. Baldwin and Hickey, {P. F.} and Berzins, {S. P.} and Mak, {J. Y.W.} and Y. Sontani and Roots, {C. M.} and T. Sidwell and A. Kallies and Z. Chen and S. N{\"u}ssing and K. Kedzierska and Mackay, {L. K.} and McColl, {S. R.} and Deenick, {E. K.} and Fairlie, {D. P.} and J. McCluskey and Goodnow, {C. C.} and Ritchie, {M. E.} and Belz, {G. T.} and Naik, {S. H.} and Pellicci, {D. G.} and Godfrey, {D. I.}",
year = "2019",
month = "11",
day = "22",
doi = "10.1126/sciimmunol.aay6039",
language = "English",
volume = "4",
journal = "Science Immunology",
issn = "2470-9468",
publisher = "American Association for the Advancement of Science (AAAS)",
number = "41",

}

Koay, HF, Su, S, Amann-Zalcenstein, D, Daley, SR, Comerford, I, Miosge, L, Whyte, CE, Konstantinov, IE, d'Udekem, Y, Baldwin, T, Hickey, PF, Berzins, SP, Mak, JYW, Sontani, Y, Roots, CM, Sidwell, T, Kallies, A, Chen, Z, Nüssing, S, Kedzierska, K, Mackay, LK, McColl, SR, Deenick, EK, Fairlie, DP, McCluskey, J, Goodnow, CC, Ritchie, ME, Belz, GT, Naik, SH, Pellicci, DG & Godfrey, DI 2019, 'A divergent transcriptional landscape underpins the development and functional branching of MAIT cells', Science Immunology, vol. 4, no. 41, 6039. https://doi.org/10.1126/sciimmunol.aay6039

A divergent transcriptional landscape underpins the development and functional branching of MAIT cells. / Koay, H. F.; Su, S.; Amann-Zalcenstein, D.; Daley, S. R.; Comerford, I.; Miosge, L.; Whyte, C. E.; Konstantinov, I. E.; d'Udekem, Y.; Baldwin, T.; Hickey, P. F.; Berzins, S. P.; Mak, J. Y.W.; Sontani, Y.; Roots, C. M.; Sidwell, T.; Kallies, A.; Chen, Z.; Nüssing, S.; Kedzierska, K.; Mackay, L. K.; McColl, S. R.; Deenick, E. K.; Fairlie, D. P.; McCluskey, J.; Goodnow, C. C.; Ritchie, M. E.; Belz, G. T.; Naik, S. H.; Pellicci, D. G.; Godfrey, D. I.

In: Science Immunology, Vol. 4, No. 41, 6039, 22.11.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A divergent transcriptional landscape underpins the development and functional branching of MAIT cells

AU - Koay, H. F.

AU - Su, S.

AU - Amann-Zalcenstein, D.

AU - Daley, S. R.

AU - Comerford, I.

AU - Miosge, L.

AU - Whyte, C. E.

AU - Konstantinov, I. E.

AU - d'Udekem, Y.

AU - Baldwin, T.

AU - Hickey, P. F.

AU - Berzins, S. P.

AU - Mak, J. Y.W.

AU - Sontani, Y.

AU - Roots, C. M.

AU - Sidwell, T.

AU - Kallies, A.

AU - Chen, Z.

AU - Nüssing, S.

AU - Kedzierska, K.

AU - Mackay, L. K.

AU - McColl, S. R.

AU - Deenick, E. K.

AU - Fairlie, D. P.

AU - McCluskey, J.

AU - Goodnow, C. C.

AU - Ritchie, M. E.

AU - Belz, G. T.

AU - Naik, S. H.

AU - Pellicci, D. G.

AU - Godfrey, D. I.

PY - 2019/11/22

Y1 - 2019/11/22

N2 - MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 "mature" MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ-producing MAIT1 cells and interleukin-17-producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)-deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

AB - MR1-restricted mucosal-associated invariant T (MAIT) cells play a unique role in the immune system. These cells develop intrathymically through a three-stage process, but the events that regulate this are largely unknown. Here, using bulk and single-cell RNA sequencing-based transcriptomic analysis in mice and humans, we studied the changing transcriptional landscape that accompanies transition through each stage. Many transcripts were sharply modulated during MAIT cell development, including SLAM (signaling lymphocytic activation molecule) family members, chemokine receptors, and transcription factors. We also demonstrate that stage 3 "mature" MAIT cells comprise distinct subpopulations including newly arrived transitional stage 3 cells, interferon-γ-producing MAIT1 cells and interleukin-17-producing MAIT17 cells. Moreover, the validity and importance of several transcripts detected in this study are directly demonstrated using specific mutant mice. For example, MAIT cell intrathymic maturation was found to be halted in SLAM-associated protein (SAP)-deficient and CXCR6-deficient mouse models, providing clear evidence for their role in modulating MAIT cell development. These data underpin a model that maps the changing transcriptional landscape and identifies key factors that regulate the process of MAIT cell differentiation, with many parallels between mice and humans.

UR - http://www.scopus.com/inward/record.url?scp=85075530693&partnerID=8YFLogxK

U2 - 10.1126/sciimmunol.aay6039

DO - 10.1126/sciimmunol.aay6039

M3 - Article

VL - 4

JO - Science Immunology

JF - Science Immunology

SN - 2470-9468

IS - 41

M1 - 6039

ER -