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    Home > Active Ingredient News > Endocrine System > Behind the scenes of type 1 diabetes: immune T cells that won't be exhausted "Nature" paper recommended

    Behind the scenes of type 1 diabetes: immune T cells that won't be exhausted "Nature" paper recommended

    • Last Update: 2022-04-29
    • Source: Internet
    • Author: User
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    Authors: Stephen J.
    Turner & Nicole L.
    La Gruta The discovery that a specific subset of immune system T cells contributes to type 1 diabetes not only sheds new light on autoimmune diseases, but may also provide new insights into new Therapy points the way
    .

    Many autoimmune diseases, including type 1 diabetes, manifest as persistent immune responses
    .

    Writing in Nature [1], Gearty et al.
    report on a specific set of T cells in the immune system that sustain this autoimmune response
    .

    These findings have important implications for the search for therapeutic modalities to modulate the immune response
    .

    One of the hallmarks of many immune responses is the generation of effector responses that enable targeted defense against infection
    .

    For example, powerful effector responses to viral infection are often mediated by the group of immune cells called CD8 T cells
    .

    This response is usually short-lived, in which CD8 T cells are activated and subsequently proliferate and differentiate into effector cells capable of killing virus-infected cells
    .

    Once the infection is cleared (usually one to two weeks), most effector T cells die, marking the end (resolution) of the defensive response
    .

    However, some T cells remain alive and generate a population of memory T cells that can respond to the same infection
    .

    But in some cases, the target is not cleared, such as in chronic viral infection (Fig.
    1a) or cancer, and T cells are only present for a period of time, after which they lose activity
    .

    This loss of immune cell activity, known as T cell exhaustion, is regulated by the expression of inhibitory receptor proteins (mediated by the transcription factor protein TOX)[2], such as PD1 and LAG3, which act as "checkpoints" Inhibit the effector response and proliferative potential of T cells [2-4]
    .

    Figure 1 | Immune cell populations vary in the duration of their defense responses.
    a, A group of immune cells called CD8 T cells are involved in short-term responses against chronic viral infection
    .

    During this process, the T cell receptor (TCR) of CD8 T cells recognizes viral fragments (ie "antigens") and expresses high levels of the transcription factor protein TCF1
    .

    When these cells are ready to mount a defense, the cells proliferate and TCF1 expression drops
    .

    They become CD8 effector T cells that kill infected host cells that present viral antigens by the major histocompatibility complex (MHC)
    .

    The immune cells quickly enter a nonfunctional state called exhaustion, becoming CD8 TPEX cells, which express the TOX protein
    .

    b, Gearty et al.
    [1] conducted a series of mouse experiments to study how the autoimmune disease type 1 diabetes arises
    .

    It has been reported that autoimmune mediator cells generated by a subset of CD8 T cells (autoimmune progenitor cells) contribute to diabetes by killing pancreatic beta cells
    .

    Although the process initially resembled defense against chronic infection, for unknown reasons, T cell depletion did not occur
    .

    A subset of autoimmune diseases, including type 1 diabetes, are caused by abnormal responses of CD8 T cells
    .

    Abnormal responses can both attack healthy tissue and perpetuate disease and immunity
    .

    In type 1 diabetes, autoreactive CD8 T cells target and attack insulin-producing islet beta cells (Fig.
    1b), resulting in abnormally elevated blood glucose [5]
    .

    Using a mouse model of type 1 diabetes, Gearty et al.
    tracked the cell fate of CD8 T cells that specifically recognize β-cell IGRP protein fragments (ie, antigens) from weeks 3 to 50
    .

    The authors monitored cells in the pancreatic draining lymph node (pLN), where cells are activated by recognizing the IGRP antigen; they also monitored cells in the pancreas, where they mount an autoimmune attack
    .

    Gearty and colleagues identified IGPR-specific CD8 T cells in the pancreatic draining lymph nodes and pancreas of 5-week-old mice
    .

    Interestingly, CD8 T cells in pancreatic lymph nodes differed from those in the pancreas at the time of onset
    .

    In pancreatic lymph nodes, these IGPR-specific CD8 T cells had high levels of TCF1 and low levels of PD1 and CD39 expression
    .

    In contrast, IGRP-specific cells in the pancreas displayed more differentiated features—low levels of TCF1 and high levels of PD1 and CD39
    .

    Among them, TCF1 is essential for the long-term survival of memory CD8 T cells because it promotes cell self-renewal [6,7]
    .

    Stem-like populations with high TCF1 expression are often observed in T cell immune responses induced by acute infections, chronic infections and tumors [6,8-10]
    .

    In addition, this group of T cells not only has the ability to self-renew, but also "gives" a more differentiated population of effector T cells and memory cells
    .

    In chronic infections and cancers, these differentiated effector cells become functionally restricted and T cell depletion occurs
    .

    Research by Gearty and colleagues corroborates this pattern, establishing that type 1 diabetes also involves a differentiation step: autoimmune progenitor cells express high levels of TCF1 and subsequently differentiate into effector T cells with low levels of TCF1 expression, the autoimmune mediator CD8 T cells
    .

    This group of cells is initially located in the pancreatic lymph nodes
    .

    They then migrate toward the pancreas, where they further differentiate and destroy pancreatic tissue, leading to disease, possibly driven by activation after antigen recognition
    .

    The study showed that mice transplanted with autoimmune progenitor cells with high levels of TCF1 expression developed type 1 diabetes, whereas mice that received autoimmune mediators with low TCF1 expression did not (perhaps because these cells were unable to long-term survival in vivo to sustain damage to pancreatic tissue)
    .

    These transplanted autoimmune progenitor cells produced a set of autoimmune progenitor cells with self-renewal ability and high TCF1 expression while producing autoimmune mediator cells.
    When these newly generated autoimmune progenitor cells were extracted from diabetic mice Transplanted into other mice, these recipient mice also developed diabetes
    .

    When the outflow of β-cell-specific autoimmune mediator CD8 T cells from pancreatic lymph is inhibited, the therapeutic autoimmune mediator CD8 T cells in the pancreas are therefore gradually reduced
    .

    These data suggest that autoimmune progenitor cells act as a self-sustaining reservoir in pancreatic lymph nodes and a source of pathogenic autoimmune mediator cells
    .

    Notably, similar types of self-renewing T cell precursor populations reported in other studies show signs of depletion under prolonged exposure to the antigen (such as chronic infection or cancer); they are called depletion T cell precursor cells (TPEX cells) [8,9,11]
    .

    Surprisingly, however, although Gearty et al.
    also observed sustained CD8 T cell responses in type 1 diabetes, these autoimmune progenitor cells remained functional while expressing high levels of TCF1
    .

    Furthermore, autoimmune mediator cells differentiated from this cell population are highly functional
    .

    Although the expression of inhibitory receptors is high (especially on cells in the pancreas), the expression of TOX, a key marker of CD8 T cell exhaustion, is low in autoimmune mediator cells [2,4]
    .

    Gene expression profiling of immune precursor cells revealed a transcriptional signature quite distinct from both conventional memory CD8 T cells and TPEX cells
    .

    The study by Gearty et al.
    further illustrates that the mechanisms that limit CD8 T cell responses in chronic infection or cancer do not apply to type 1 diabetes, or at least not in the animal models used in this study
    .

    Two major questions arise from this study: Is this group of autoimmune CD8 T cells a common driver of persistent autoimmune CD8 T cell responses? If so, why is the depletion program not initiated under chronic exposure to self-antigens recognized by these cells? Answering these questions will help develop new therapies for CD8 T cell-mediated diseases
    .

    The authors suggest that drugs that block the lymphatic outflow of CD8 T cells from the pancreas may offer new hope for people with type 1 diabetes
    .

    However, treatment can only be effective when these CD8 T cells, which recognize self-antigens, are generated soon after they are generated
    .

    Taking advantage of the vastly different molecular characteristics between autoimmune progenitor cells and conventional memory T cells and TPEX cells, it is possible to selectively clear or induce exhaustion programs to suppress pathogenic immune responses
    .

    On the other hand, understanding how these autoimmune cells are protected from exhaustion programs may help provide insights that help develop persistent antigen-specific responses to cancer
    .

    1038/d41586-021-03800-z Click to read the original text to view the English text promotion | Tsinghua University Shenzhen International Graduate School 2022 Global Recruitment! Click the applet below to view the copyright statement: This article is translated by Springer Nature Shanghai Office
    .

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    .

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