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Published on: January 24, 2016
Interferon regulatory factor 4 controls effector functions of CD8+ memory T cells
Aenne Harberts1, Constantin Schmidt1, Joanna Schmid1
1Institute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Insights
The transcription factor IRF4 is crucial for CD8+ T cell responses. While not essential for survival, IRF4 is required for the effective reactivation and function of CD8+ memory T cells, particularly tissue-resident memory (TRM) cells.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Interferon regulatory factor 4 (IRF4) is vital for CD8+ T cell effector functions.
- The role of IRF4 in CD8+ memory T cells remains largely unexplored.
- CD8+ T cells differentiate into effector cells and memory cells after infection.
Purpose of the Study:
- To investigate the function of IRF4 in maintaining the differentiation state and survival of CD8+ memory T cells.
- To determine IRF4's role in the reactivation and effector function of memory CD8+ T cells upon secondary infection.
- To assess the specific role of IRF4 in CD8+ tissue-resident memory (TRM) cells.
Main Methods:
- Used a tamoxifen-inducible Irf4 knockout mouse model.
- Infected mice with ovalbumin-recombinant Listeria.
- Induced Irf4 knockout after pathogen clearance and analyzed CD8+ T cell populations and function upon re-exposure.
Main Results:
- Loss of IRF4 altered CD8+ memory T cell phenotype but did not affect overall population size.
- IRF4-deficient CD8+ memory T cells exhibited impaired expansion and effector function upon secondary infection.
- CD8+ TRM cells expressed higher IRF4 levels than effector memory T cells, and IRF4 deficiency reduced CD8+ TRM populations.
Conclusions:
- IRF4 is essential for the effective reactivation of CD8+ memory T cells, but not for their general survival.
- IRF4 plays a critical role in the formation and maintenance of CD8+ TRM cells.
Abstract:
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 model with 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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