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Nature: BATF3 improves T cell memory response and the efficacy of immunotherapy

2020-11-04
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The basic leucine zipper transcription factor ATF-like 3 (BATF3) plays a key role in the development of conventional type I dendritic cells, and this type of dendritic cells plays a key role in the cross-presentation of pathogens and CD8+ T cell-mediated It is necessary in immune response such as tumor immunity. During the immune response mediated by CD8+ T cells, T lymphocytes undergo initial activation/priming, mass proliferation, subpopulation differentiation, population contraction, and stable memory pool formation.
Recently, a researcher from the University of Würzburg in Germany, Marco Ataide, et al. demonstrated the role of BATF3 and clarified an important step in the molecular regulation of CD8+ T cell survival and memory, and published it in the journal Nature Immunology on September 28. The article shows that BATF3 is expressed briefly in the first day after T cell activation, and can have a continuous effect on the T cell itself. T cells lacking Batf3 expression can proliferate and differentiate normally, but then the number drops sharply and the memory response is weakened. Vice versa, overexpression of BATF3 prolongs the survival time of CD8+ T cells and promotes their transition to memory. This is because in the signal pathway, BATF3 regulates the apoptosis and survival of T cells through the pro-apoptotic factor BIM. And if this mechanism can be applied, then the survival and memory of CD8+ T cells can be programmed and modified, thereby prolonging the time of action of this key tumor immune cell, so that the tumor immune response can resist future threats.

BATF3 improves T cell memory response
Nature: BATF3 improves T cell memory response and is expected to improve the efficacy of immunotherapy

Memory T cell

The interaction between T cells and classical dendritic cells is a feature of the mammalian immune system. In this classical model of interaction, classical dendritic cells present pathogen antigens to CD8+ T cells, and CD8+ T cells recognize the antigen and perform rapid clonal expansion. This expanded effector T cell population can recognize and kill infected cells in the host.
With the successful elimination of pathogens, most of the expanded T cells undergo apoptosis mediated by the pro-apoptotic factor BIM (Bcl2l11). However, a subset of these T cells still exist as memory T cells after the initial pathogen clearance. If the host is infected again, these memory cells can quickly attack the same pathogen.

The effect of BATF on CD8+ T cells

The researchers used BATF3-deficient mice to compare with wild-type mice to explore the intrinsic effect of BATF3 on CD8+ T cells. Studies have shown that in a series of primary and secondary infections in wild-type and BATF3 knockout mice, the CD8+ T cells of these mice have normal phenotypic functions, including the ability to continuously produce effector cytokines. However, 6 days after the secondary infection, the abundance of antigen-specific CD8+ T cells in BATF3 knockout mice was greatly reduced, which is consistent with the results of the verification experiment. This indicates that an inherent T cell function of BATF3 seems to be essential for the memory development or re-response ability of CD8+ T cells.
Next, the researchers began to explore whether this effect on the functional phenotype of cells was due to the lack of BATF3 leading to systolic memory loss or the lack of BATF3 leading to defects in the recall response process, or whether BATF3 affected T through both pathways. The memory response of the cell.
Through a series of experiments, they found that all memory CD8+ T cell subpopulations, including TCM (central memory), TEM (effector memory) and TPM (peripheral memory) cells, are affected by the loss of BATF3. The rat was exhausted. In addition, the researchers also found that the cellular efficiency of the memory response in BATF3-deficient T cells was reduced. Therefore, BATF3 is critical to the transformation and quality of memory CD8+ T cells.
Researchers found that BATF3 is critical to the transformation and quality of memory CD8+ T cells.

BATF3
BATF3  (Image source: Nature Immunology)

BIM mediates impaired T cell memory response


After gene set enrichment analysis, mRNA knockout, and overexpression experiments, the researchers determined that the pro-apoptotic factor BIM, which regulates CD8+ T cell contraction, is the downstream mediator of the impaired memory response of BATF3-deficient T cells. After synthesis, T cells lacking BATF3 showed normal expansion and differentiation, but their apoptosis was intensified and memory response was weakened. On the contrary, the overexpression of BATF3 in CD8+ T cells promotes their survival and excessive memory. These results establish that BATF3 is a key regulator of CD8+ T cell memory.
This research combines basic research with applied medicine and may help to use the patient’s immune system to develop better cancer treatments, such as the so-called CAR-T cell therapy. In CAR-T cell therapy, T cells are extracted from the patient’s blood and then genetically modified to express chimeric antigen receptor (CAR) molecules. This genetic modification allows these T cells to attack tumor cells that were previously undetectable by biochemical methods. These genetically modified T cells are then transferred back to the patient. At present, CAR-T cells have been successfully used to treat diseases such as B-cell lymphoma, among which B-cell lymphoma is a malignant disease of the lymphatic system. Now, the Kastenmueller team and Professor Hudecek are planning to improve CAR-T cells to improve the survival rate of patients, thereby increasing the efficiency of treatment.

Reference materials:
Marco A. Ataide et al. BATF3 programs CD8+ T cell memory. Nature Immunology, 2020,doi:10.1038/s41590-020-0786-2

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