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Bcl-2 Is Necessary to Counteract Bim and Promote Survival of TCRαβ+CD8αα+ Intraepithelial Lymphocyte Precursors in the Thymus

Sharmila Shanmuganad, Sarah A. Hummel, Vivian Varghese and David A. Hildeman
J Immunol February 1, 2022, 208 (3) 651-659; DOI: https://doi.org/10.4049/jimmunol.2100975
Sharmila Shanmuganad
*Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH; and
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Sarah A. Hummel
†Division of Immunobiology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH
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Vivian Varghese
†Division of Immunobiology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH
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David A. Hildeman
*Immunology Graduate Program, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH; and
†Division of Immunobiology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH
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Key Points

  • Bcl-2 promotes survival of thymic precursors of TCRαβ+CD8αα+ IEL by antagonizing Bim.

  • CD122+ DN IELp that coexpress Runx3 and α4β7 display the highest Bcl-2 dependence.

  • Mice with thymic loss of Bcl-2 have an almost complete loss of gut TCRαβ+CD8αα+ IEL.

Abstract

The precursors of TCRαβ+CD8αα+ intraepithelial lymphocytes (IEL) arise in the thymus through a complex process of agonist selection. We and others have shown that the proapoptotic protein, Bim, is critical to limit the number of thymic IEL precursors (IELp), as loss of Bim at the CD4+CD8+ double-positive stage of development drastically increases IELp. The factors determining this cell death versus survival decision remain largely unknown. In this study, we used CD4CreBcl2f/f mice to define the role of the antiapoptotic protein Bcl-2 and CD4CreBcl2f/fBimf/f mice to determine the role of Bcl-2 in opposing Bim to promote survival of IELp. First, in wild-type mice, we defined distinct subpopulations within PD-1+CD122+ IELp, based on their expression of Runx3 and α4β7. Coexpression of α4β7 and Runx3 marked IELp that were most dependent upon Bcl-2 for survival. Importantly, the additional loss of Bim restored Runx3+α4β7+ IELp, showing that Bcl-2 antagonizes Bim to enable IELp survival. Further, the loss of thymic IELp in CD4CreBcl2f/f mice also led to a dramatic loss of IEL in the gut, and the additional loss of Bim restored gut IEL. The loss of gut IEL was due to both reduced seeding by IELp from the thymus as well as a requirement for Bcl-2 for peripheral IEL survival. Together, these findings highlight subset-specific and temporal roles for Bcl-2 in driving the survival of TCRαβ+CD8αα+ IEL and thymic IELp.

This article is featured in Top Reads, p.

Footnotes

  • This work was supported by U.S. Public Health Service (National Institutes of Health) Grant AI057753, by generous startup funds from the Cincinnati Children’s Hospital Research Foundation, and in part by the Center for Rheumatic Disease Research (National Institutes of Health AR070549).

  • S.S. designed and performed experiments and analyzed data. S.A.H. performed certain experiments and helped with genotyping of mice. V.V. helped with genotyping of mice. S.S. and D.A.H. wrote the manuscript.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article

    DN
    double-negative
    DP
    double-positive
    IEL
    intraepithelial lymphocyte
    IELp
    intraepithelial lymphocyte precursor
    PD-1
    programmed cell death 1
    TP
    triple-positive
    Treg
    regulatory T cell
    WT
    wild-type

  • Received October 12, 2021.
  • Accepted November 16, 2021.
  • Copyright © 2022 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (3)
The Journal of Immunology
Vol. 208, Issue 3
1 Feb 2022
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Bcl-2 Is Necessary to Counteract Bim and Promote Survival of TCRαβ+CD8αα+ Intraepithelial Lymphocyte Precursors in the Thymus
Sharmila Shanmuganad, Sarah A. Hummel, Vivian Varghese, David A. Hildeman
The Journal of Immunology February 1, 2022, 208 (3) 651-659; DOI: 10.4049/jimmunol.2100975

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Bcl-2 Is Necessary to Counteract Bim and Promote Survival of TCRαβ+CD8αα+ Intraepithelial Lymphocyte Precursors in the Thymus
Sharmila Shanmuganad, Sarah A. Hummel, Vivian Varghese, David A. Hildeman
The Journal of Immunology February 1, 2022, 208 (3) 651-659; DOI: 10.4049/jimmunol.2100975
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