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Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8+ T cells.

Publication ,  Journal Article
Helm, EY; Zelenka, T; Cismasiu, VB; Islam, S; Silvane, L; Zitti, B; Holmes, TD; Drashansky, TT; Kwiatkowski, AJ; Tao, C; Dean, J; Chen, X ...
Published in: Science immunology
April 2023

The networks of transcription factors (TFs) that control intestinal-resident memory CD8+ T (TRM) cells, including multipotency and effector programs, are poorly understood. In this work, we investigated the role of the TF Bcl11b in TRM cells during infection with Listeria monocytogenes using mice with post-activation, conditional deletion of Bcl11b in CD8+ T cells. Conditional deletion of Bcl11b resulted in increased numbers of intestinal TRM cells and their precursors as well as decreased splenic effector and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of Bcl11b-/- circulating precursors, with no major alterations in their programs. Bcl11b-/- TRM cells had altered transcriptional programs, with diminished expression of multipotent/multifunctional (MP/MF) program genes, including Tcf7, and up-regulation of the effector program genes, including Prdm1. Bcl11b also limits the expression of Ahr, another TF with a role in intestinal CD8+ TRM cell differentiation. Deregulation of TRM programs translated into a poor recall response despite TRM cell accumulation in the intestine. Reduced expression of MP/MF program genes in Bcl11b-/- TRM cells was linked to decreased chromatin accessibility and a reduction in activating histone marks at these loci. In contrast, the effector program genes displayed increased activating epigenetic status. These findings demonstrate that Bcl11b is a frontrunner in the tissue residency program of intestinal memory cells upstream of Tcf1 and Blimp1, promoting multipotency and restricting the effector program.

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Published In

Science immunology

DOI

EISSN

2470-9468

ISSN

2470-9468

Publication Date

April 2023

Volume

8

Issue

82

Start / End Page

eabn0484

Related Subject Headings

  • Tumor Suppressor Proteins
  • Transcription Factors
  • Repressor Proteins
  • Mice
  • Intestines
  • Cell Differentiation
  • CD8-Positive T-Lymphocytes
  • Animals
  • 3204 Immunology
  • 3202 Clinical sciences
 

Citation

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Helm, E. Y., Zelenka, T., Cismasiu, V. B., Islam, S., Silvane, L., Zitti, B., … Avram, D. (2023). Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8+ T cells. Science Immunology, 8(82), eabn0484. https://doi.org/10.1126/sciimmunol.abn0484
Helm, Eric Y., Tomas Zelenka, Valeriu B. Cismasiu, Shamima Islam, Leonardo Silvane, Beatrice Zitti, Tim D. Holmes, et al. “Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8+ T cells.Science Immunology 8, no. 82 (April 2023): eabn0484. https://doi.org/10.1126/sciimmunol.abn0484.
Helm EY, Zelenka T, Cismasiu VB, Islam S, Silvane L, Zitti B, et al. Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8+ T cells. Science immunology. 2023 Apr;8(82):eabn0484.
Helm, Eric Y., et al. “Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8+ T cells.Science Immunology, vol. 8, no. 82, Apr. 2023, p. eabn0484. Epmc, doi:10.1126/sciimmunol.abn0484.
Helm EY, Zelenka T, Cismasiu VB, Islam S, Silvane L, Zitti B, Holmes TD, Drashansky TT, Kwiatkowski AJ, Tao C, Dean J, Obermayer AN, Chen X, Keselowsky BG, Zhang W, Huo Z, Zhou L, Sheridan BS, Conejo-Garcia JR, Shaw TI, Bryceson YT, Avram D. Bcl11b sustains multipotency and restricts effector programs of intestinal-resident memory CD8+ T cells. Science immunology. 2023 Apr;8(82):eabn0484.

Published In

Science immunology

DOI

EISSN

2470-9468

ISSN

2470-9468

Publication Date

April 2023

Volume

8

Issue

82

Start / End Page

eabn0484

Related Subject Headings

  • Tumor Suppressor Proteins
  • Transcription Factors
  • Repressor Proteins
  • Mice
  • Intestines
  • Cell Differentiation
  • CD8-Positive T-Lymphocytes
  • Animals
  • 3204 Immunology
  • 3202 Clinical sciences