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    Home > Active Ingredient News > Immunology News > Sci Immunol | The key role of immune checkpoints and DNA repair damage in the formation of early memory T cells

    Sci Immunol | The key role of immune checkpoints and DNA repair damage in the formation of early memory T cells

    • Last Update: 2021-03-25
    • Source: Internet
    • Author: User
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    Written by Uncle Bao | Qi memory T cells are essential in the human body's fight against specific infections and tumors.

    Regarding the differentiation process of memory T cells, researchers have reported and elaborated on many aspects such as transcriptional regulation, metabolism and epigenetics.

    However, in the process of memory T cell differentiation, there are still key questions to be answered: 1) Are there really stem-like memory T cells? If so, what are the molecular characteristics of these cells? 2) How do long-existing memory T cells keep their cell state and genetic information stable? On January 15, 2021, E.
    John Wherry's group from the University of Pennsylvania published an article titled Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage in Science Immunology.
    The study revealed that there is a subpopulation of memory T cells that has a stronger stemness than the generalized memory T cells (IL-7Ra+), and this subpopulation has two distinct molecular characteristics: 1) Contrast effector T cells and Other memory T cell precursor cells have higher expression of immune checkpoints (such as PD-1 and LAG-3); 2) can better protect their genome from damage.

    The researchers first used flow cytometry and single-cell sequencing analysis and found that in the early stages of acute infection, CD62Lhi T cell subsets highly expressed the core transcription factors TCF-1/LEF-1 of memory T cells, and the anti-apoptotic molecule Bcl- 2 and important chemokine receptors CXCR3 and CXCR4.

    Interestingly, even in the early stage of acute infection, the T cell subset of CD62Lhi also highly expresses the transcription factors TOX and Eomes that are traditionally considered to play a central role in T cell exhaustion (Figure 1).

    At the same time, these cells do not express terminal effector T cell molecules, such as the transcription factors T-bet and Blimp1, and the markers KLRG1 and KLRD1.

    Furthermore, although these cells express Granzyme B at a low level, they secrete more cytokines, especially IL-2, which promotes the expansion of T cells (Figure 1).

    Furthermore, the researchers found that this cell subset is distributed in multiple peripheral lymphoid organs, and it is especially enriched in lymph nodes (Figure 1).

    Figure 1.
    After identifying the stem CD8 T cell subsets of CD62Lhi in the early stage of acute infection, the researchers described the CD62Lhi T cell subsets, Naïve T cells and IL-7Ra+ memory cells at the transcriptome level.
    The difference between precursors, and identification of about 80 CD62Lhi signature molecules (core signature).

    At the same time, the researchers also proved that TCF-1 is a molecule necessary for the formation of CD62Lhi.

    Furthermore, the researchers found that the CD8 T cell subset of CD62Lhi has long-term self-renewal, differentiation and secondary response functions, and can differentiate into IL-7Ra+ memory T cells in the traditional sense.
    Therefore, in terms of cell function, This group of CD62Lhi T cells are more like memory cells with the characteristics of stem cells.

    Memory T cells can maintain stable self-renewal and secondary response for several years or even decades in the body, so how to maintain these dry memory T cells has become an important issue.

    Researchers first discovered that this group of stem-like CD62Lhi T cells can better protect their genome.

    Under the destruction of ultraviolet radiation, the degree of genome fragmentation of CD62Lhi T cells is much lower than that of effector T cells.

    Furthermore, the researchers observed that CD62Lhi T cells have a higher γH2AX signal under the induction of genomic damage, suggesting that these cells have a better response to DNA damage repair.

    At the same time, researchers also found that the telomerase activity in CD62Lhi T cells is higher, suggesting that these cells have better telomere protection.

    In addition, the researchers used the DNA damage drug Doxorubicin to induce T cell DNA damage during the acute infection period, and then found that the CD62Lhi stem memory cell subpopulation can better maintain the population stability.

    A stronger DNA damage repair mechanism gives CD62Lhi stem T cells a better internal genome protection mechanism, so how do these cells maintain a stable cell state under long-term external signal stimulation? Researchers have further targeted immune checkpoint molecules.

    Researchers first discovered that multiple immune checkpoint molecules, such as PD-1, CTLA-4, LAG-3, CD160, CD200R, etc.
    , are all highly expressed in this CD62Lhi subgroup (except TIM-3 and 2B4).
    ).

    Furthermore, the researchers locked the PD-1 and LAG-3 molecules, using the wild-type and PD-1/LAG-3 double knockout virus-specific T cell cotransformation system, and found that PD-1/LAG-3 In the double-knockout T cells, the proportion of the stem T cells was significantly reduced, and the secondary/tertiary response became worse.

    Therefore, the researchers proved that the traditional immune checkpoint molecules, which are characteristic of T cell exhaustion, play a key role in protecting the formation of dry memory T cells in acute infections.

    The research further deepened the understanding of stem memory T cells, and at the same time discovered the key role of the genome protection mechanism and immune checkpoint signals on the stem memory cell population.

    Further details of the mechanism remain to be studied, and the cracking of this mechanism may radiate a number of important immunological issues, such as the aging process of effective immune memory, such as the long-term response effect of vaccines, and how to deal with cancer treatment.
    Try to preserve the response ability of T cells under chemotherapy conditions. Original link: https://immunology.
    sciencemag.
    org/content/6/55/eabe3702.
    full
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