Interferon regulatory factor 4 controls effector functions of CD8⁺ memory T cells

The transcription factor IRF4 is required for CD8⁺ T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8⁺ T cell responses. The function of IRF4 in memory CD8⁺ T cells yet needs to be explored. To investigate the role of IRF4 for maintaining dif...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 118; no. 16; pp. 1 - 10
Main Authors Harberts, Aenne, Schmidt, Constantin, Schmid, Joanna, Reimers, Daniel, Koch-Nolte, Friedrich, Mittrücker, Hans-Willi, Raczkowski, Friederike
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 20.04.2021
Subjects
Biological Sciences
CD8 antigen
Cell activation
Cell differentiation
Cell proliferation
Differentiation (biology)
Effector cells
Immunological memory
Interferon
Interferon regulatory factor
Interferon regulatory factor 4
Listeria
Lymphocytes
Lymphocytes T
Memory cells
Ovalbumin
Pathogens
Reduction
Survival
Tamoxifen
Listeria monocytogenes
CD8+ T cells
interferon regulatory factor 4
memory T cells
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Summary:The transcription factor IRF4 is required for CD8⁺ T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8⁺ T cell responses. The function of IRF4 in memory CD8⁺ T cells yet needs to be explored. To investigate the role of IRF4 for maintaining differentiation state and survival of CD8⁺ memory T cells, we used a mouse modelwith tamoxifen-inducible Irf4 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced Irf4 knockout after clearance of the pathogen. Loss of IRF4 resulted in phenotypical changes of CD8⁺ memory T cells but did not cause a reduction of the total memory T cell population. However, upon reencounter of the pathogen, CD8⁺ memory T cells showed impaired expansion and acquisition of effector functions. When compared to CD8⁺ effector memory T cells, CD8⁺ tissue-resident memory T cells (TRM cells) expressed higher IRF4 levels. Mice with constitutive Irf4 knockout had diminished CD8⁺ TRM-cell populations, and tamoxifen-induced Irf4 deletion caused a reduction of this cell population. In conclusion, our results demonstrate that IRF4 is required for effective reactivation but not for general survival of CD8⁺ memory T cells. Formation and maintenance of CD8⁺ TRM cells, in contrast, appear to depend on IRF4.
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1H.-W.M. and F.R. contributed equally to this work.
Author contributions: A.H., H.-W.M., and F.R. designed research; A.H., C.S., J.S., D.R., and F.R. performed research; F.K.-N. contributed new reagents/analytic tools; A.H., C.S., H.-W.M., and F.R. analyzed data; and A.H., H.-W.M., and F.R. wrote the paper.
Edited by Tak W. Mak, University of Toronto, Toronto, Canada, and approved February 3, 2021 (received for review July 10, 2020)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2014553118