Type III interferon drives thymic B cell activation and regulatory T cell generation

Ryan J. Martinez; Elise R. Breed; Yosan Worota; Katherine M. Ashby; Matouš Vobořil; Tailor Mathes; Oscar C. Salgado; Christine H. O’Connor; Sergei V. Kotenko; Kristin A. Hogquist

doi:10.1073/pnas.2220120120

Type III interferon drives thymic B cell activation and regulatory T cell generation

Ryan J. Martinez, Elise R. Breed, Yosan Worota, Katherine M. Ashby, Matouš Vobořil, Tailor Mathes, Oscar C. Salgado, Christine H. O’Connor, Sergei V. Kotenko, Kristin A. Hogquist

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

The activation of thymic B cells is critical for their licensing as antigen presenting cells and resulting ability to mediate T cell central tolerance. The processes leading to licensing are still not fully understood. By comparing thymic B cells to activated Peyer’s patch B cells at steady state, we found that thymic B cell activation starts during the neonatal period and is characterized by TCR/CD40-dependent activation, followed by immunoglobulin class switch recombination (CSR) without forming germinal centers. Transcriptional analysis also demonstrated a strong interferon signature, which was not apparent in the periphery. Thymic B cell activation and CSR were primarily dependent on type III IFN signaling, and loss of type III IFN receptor in thymic B cells resulted in reduced thymocyte regulatory T cell (T_reg) development. Finally, from TCR deep sequencing, we estimate that licensed B cells induce development of a substantial fraction of the T_reg cell repertoire. Together, these findings reveal the importance of steady-state type III IFN in generating licensed thymic B cells that induce T cell tolerance to activated B cells.

Original language	English (US)
Article number	e2220120120
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	120
Issue number	9
DOIs	https://doi.org/10.1073/pnas.2220120120
State	Published - Feb 28 2023

Bibliographical note

Funding Information:
We thank J. Ding and L. Qian for technical assistance, J. Motl from the University Flow Cytometry Resource for cell sorting, J. Moon for providing tetramer reagents, the University of Minnesota Genomics Center for assistance with RNA-seq, scRNA-seq and TCR analysis and the University of Minnesota Research Animal Resources for animal husbandry. The scRNA seq data reported here were previously described in the thesis work of O.C.S. Matous Voboril is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute (CRI Award # CRI4536). This project was supported by the NIH (grant nos. R37 AI39560 and P01 AI35296 to K.A.H., T32 AI007313 to K.M.A. and E.R.B., and F30 AI131483 and T32 GM008244 to E.R.B.).

Funding Information:
seq data reported here were previously described in the thesis work of O.C.S. Matous Voboril is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute (CRI Award # CRI4536). This project was supported by the NIH (grant nos. R37 AI39560 and P01 AI35296 to K.A.H., T32 AI007313 to K.M.A. and E.R.B., and F30 AI131483 and T32 GM008244 to E.R.B.).

Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.

Keywords

T cell selection
central tolerance
thymic B cells
type III IFN

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

Access

10.1073/pnas.2220120120

OpenUrl availability

Full text

Cite this

Martinez, R. J., Breed, E. R., Worota, Y., Ashby, K. M., Vobořil, M., Mathes, T., Salgado, O. C., O’Connor, C. H., Kotenko, S. V., & Hogquist, K. A. (2023). Type III interferon drives thymic B cell activation and regulatory T cell generation. Proceedings of the National Academy of Sciences of the United States of America, 120(9), Article e2220120120. https://doi.org/10.1073/pnas.2220120120

Martinez, RJ, Breed, ER, Worota, Y, Ashby, KM, Vobořil, M, Mathes, T, Salgado, OC, O’Connor, CH, Kotenko, SV & Hogquist, KA 2023, 'Type III interferon drives thymic B cell activation and regulatory T cell generation', Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 9, e2220120120. https://doi.org/10.1073/pnas.2220120120

@article{836a30a3634a4b768bcf569aad919f0b,

title = "Type III interferon drives thymic B cell activation and regulatory T cell generation",

abstract = "The activation of thymic B cells is critical for their licensing as antigen presenting cells and resulting ability to mediate T cell central tolerance. The processes leading to licensing are still not fully understood. By comparing thymic B cells to activated Peyer{\textquoteright}s patch B cells at steady state, we found that thymic B cell activation starts during the neonatal period and is characterized by TCR/CD40-dependent activation, followed by immunoglobulin class switch recombination (CSR) without forming germinal centers. Transcriptional analysis also demonstrated a strong interferon signature, which was not apparent in the periphery. Thymic B cell activation and CSR were primarily dependent on type III IFN signaling, and loss of type III IFN receptor in thymic B cells resulted in reduced thymocyte regulatory T cell (Treg) development. Finally, from TCR deep sequencing, we estimate that licensed B cells induce development of a substantial fraction of the Treg cell repertoire. Together, these findings reveal the importance of steady-state type III IFN in generating licensed thymic B cells that induce T cell tolerance to activated B cells.",

keywords = "T cell selection, central tolerance, thymic B cells, type III IFN",

author = "Martinez, {Ryan J.} and Breed, {Elise R.} and Yosan Worota and Ashby, {Katherine M.} and Matou{\v s} Vobo{\v r}il and Tailor Mathes and Salgado, {Oscar C.} and O{\textquoteright}Connor, {Christine H.} and Kotenko, {Sergei V.} and Hogquist, {Kristin A.}",

note = "Funding Information: We thank J. Ding and L. Qian for technical assistance, J. Motl from the University Flow Cytometry Resource for cell sorting, J. Moon for providing tetramer reagents, the University of Minnesota Genomics Center for assistance with RNA-seq, scRNA-seq and TCR analysis and the University of Minnesota Research Animal Resources for animal husbandry. The scRNA seq data reported here were previously described in the thesis work of O.C.S. Matous Voboril is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute (CRI Award # CRI4536). This project was supported by the NIH (grant nos. R37 AI39560 and P01 AI35296 to K.A.H., T32 AI007313 to K.M.A. and E.R.B., and F30 AI131483 and T32 GM008244 to E.R.B.). Funding Information: seq data reported here were previously described in the thesis work of O.C.S. Matous Voboril is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute (CRI Award # CRI4536). This project was supported by the NIH (grant nos. R37 AI39560 and P01 AI35296 to K.A.H., T32 AI007313 to K.M.A. and E.R.B., and F30 AI131483 and T32 GM008244 to E.R.B.). Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s). Published by PNAS.",

year = "2023",

month = feb,

day = "28",

doi = "10.1073/pnas.2220120120",

language = "English (US)",

volume = "120",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "9",

}

TY - JOUR

T1 - Type III interferon drives thymic B cell activation and regulatory T cell generation

AU - Martinez, Ryan J.

AU - Breed, Elise R.

AU - Worota, Yosan

AU - Ashby, Katherine M.

AU - Vobořil, Matouš

AU - Mathes, Tailor

AU - Salgado, Oscar C.

AU - O’Connor, Christine H.

AU - Kotenko, Sergei V.

AU - Hogquist, Kristin A.

N1 - Funding Information: We thank J. Ding and L. Qian for technical assistance, J. Motl from the University Flow Cytometry Resource for cell sorting, J. Moon for providing tetramer reagents, the University of Minnesota Genomics Center for assistance with RNA-seq, scRNA-seq and TCR analysis and the University of Minnesota Research Animal Resources for animal husbandry. The scRNA seq data reported here were previously described in the thesis work of O.C.S. Matous Voboril is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute (CRI Award # CRI4536). This project was supported by the NIH (grant nos. R37 AI39560 and P01 AI35296 to K.A.H., T32 AI007313 to K.M.A. and E.R.B., and F30 AI131483 and T32 GM008244 to E.R.B.). Funding Information: seq data reported here were previously described in the thesis work of O.C.S. Matous Voboril is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute (CRI Award # CRI4536). This project was supported by the NIH (grant nos. R37 AI39560 and P01 AI35296 to K.A.H., T32 AI007313 to K.M.A. and E.R.B., and F30 AI131483 and T32 GM008244 to E.R.B.). Publisher Copyright: Copyright © 2023 the Author(s). Published by PNAS.

PY - 2023/2/28

Y1 - 2023/2/28

N2 - The activation of thymic B cells is critical for their licensing as antigen presenting cells and resulting ability to mediate T cell central tolerance. The processes leading to licensing are still not fully understood. By comparing thymic B cells to activated Peyer’s patch B cells at steady state, we found that thymic B cell activation starts during the neonatal period and is characterized by TCR/CD40-dependent activation, followed by immunoglobulin class switch recombination (CSR) without forming germinal centers. Transcriptional analysis also demonstrated a strong interferon signature, which was not apparent in the periphery. Thymic B cell activation and CSR were primarily dependent on type III IFN signaling, and loss of type III IFN receptor in thymic B cells resulted in reduced thymocyte regulatory T cell (Treg) development. Finally, from TCR deep sequencing, we estimate that licensed B cells induce development of a substantial fraction of the Treg cell repertoire. Together, these findings reveal the importance of steady-state type III IFN in generating licensed thymic B cells that induce T cell tolerance to activated B cells.

AB - The activation of thymic B cells is critical for their licensing as antigen presenting cells and resulting ability to mediate T cell central tolerance. The processes leading to licensing are still not fully understood. By comparing thymic B cells to activated Peyer’s patch B cells at steady state, we found that thymic B cell activation starts during the neonatal period and is characterized by TCR/CD40-dependent activation, followed by immunoglobulin class switch recombination (CSR) without forming germinal centers. Transcriptional analysis also demonstrated a strong interferon signature, which was not apparent in the periphery. Thymic B cell activation and CSR were primarily dependent on type III IFN signaling, and loss of type III IFN receptor in thymic B cells resulted in reduced thymocyte regulatory T cell (Treg) development. Finally, from TCR deep sequencing, we estimate that licensed B cells induce development of a substantial fraction of the Treg cell repertoire. Together, these findings reveal the importance of steady-state type III IFN in generating licensed thymic B cells that induce T cell tolerance to activated B cells.

KW - T cell selection

KW - central tolerance

KW - thymic B cells

KW - type III IFN

UR - http://www.scopus.com/inward/record.url?scp=85148390007&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85148390007&partnerID=8YFLogxK

U2 - 10.1073/pnas.2220120120

DO - 10.1073/pnas.2220120120

M3 - Article

C2 - 36802427

AN - SCOPUS:85148390007

SN - 0027-8424

VL - 120

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 9

M1 - e2220120120

ER -

Type III interferon drives thymic B cell activation and regulatory T cell generation

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this