inzicht - Immunology - # Autoimmune disease development in human immune system (HIS) mice

Follicular Helper and Peripheral Helper T Cells Induce Autoimmune Disease in Human Immune System Mice

Q: How do the differences in thymic selection between Mu/Hu and Hu/Hu mice impact the functional properties and pathogenicity of Tfh-like and Tph-like cells beyond their ability to help B cells?

The differences in thymic selection between Mu/Hu and Hu/Hu mice have significant implications for the functional properties and pathogenicity of Tfh-like and Tph-like cells. In Mu/Hu mice, where human T cells develop in the native murine thymus, there is a lack of normal negative selection for self-antigens due to the absence of a normal thymic structure, including a paucity of medullary epithelial cells. This results in the generation of T cells that are not tolerized to murine antigens, leading to their recognition of murine peptides presented on human APCs. These T cells may react with human APCs loaded with murine antigens, including human B cells, in a manner resembling an alloresponse, potentially activating B cells and inducing polyclonal class-switched antibody responses, including autoantibodies. On the other hand, in Hu/Hu mice, where T cells develop in a human fetal thymus graft, there is normal negative selection for self-antigens, resulting in T cells that are tolerized to tissue-restricted murine antigens presented on human APCs. This leads to more effective interactions between T cells and autologous human APCs and B cells, optimizing T cell expansion and B cell differentiation. The Tfh-like and Tph-like cells generated in an autologous human thymus graft interact more effectively with peripheral B cells and other APCs, likely due to positive selection on the same HLA molecules as those in the peripheral APCs, resulting in enhanced T cell expansion, increased CD11c expression on B cells, and eventually disease development.

Q: How do the potential mechanisms by which B cell depletion accelerates disease development in HIS mice, if antibodies are not the primary drivers?

The potential mechanisms by which B cell depletion accelerates disease development in HIS mice, even when antibodies are not the primary drivers, can be attributed to the regulatory role of B cells in autoimmune disease. While B cells and antibodies may not be required for disease development, B cells can play a role in regulating immune responses and maintaining tolerance. In the absence of B cells, there may be a dysregulation of immune responses, leading to unchecked activation of T cells and other effector cells. B cells have been shown to have regulatory functions in autoimmune diseases, including the production of regulatory cytokines and the modulation of T cell responses. By depleting B cells, the regulatory mechanisms that normally suppress autoimmune responses may be disrupted, leading to increased activation of autoreactive T cells and other effector cells. This dysregulation can accelerate the development of autoimmune disease in HIS mice, even in the absence of a direct role for antibodies in driving the pathology.

Q: What are the specific murine antigens recognized by the autoreactive T cells that develop in the Mu/Hu mice, and how do they contribute to the induction of autoimmunity when presented on human APCs?

The autoreactive T cells that develop in the Mu/Hu mice recognize specific murine antigens that are presented on human APCs, contributing to the induction of autoimmunity in these mice. The lack of tolerance to murine antigens in the primary Mu/Hu mice reflects the absence of normal negative selection in the native murine thymus, resulting in the generation of T cells that are not tolerized to murine antigens. These T cells may recognize tissue-restricted murine antigens that are presented on human APCs, leading to their activation and the initiation of autoimmune responses. The specific murine antigens recognized by the autoreactive T cells in Mu/Hu mice may include peptides derived from tissue-specific proteins or antigens that are normally expressed by murine cells. When these murine antigens are presented on human APCs, the autoreactive T cells can interact with the HLA molecules on the APCs, leading to T cell activation and the production of pro-inflammatory cytokines. This activation of T cells by murine antigens presented on human APCs can trigger an autoimmune response, resulting in tissue damage and the development of autoimmune disease in the Mu/Hu mice.

Belangrijkste concepten

Follicular helper-like (Tfh) and peripheral helper-like (Tph) T cells developing in HIS mice can induce autoimmune disease, with Tfh-like cells being more prominent in HIS mice with a mouse thymus and associated with higher levels of IgG antibodies.

Samenvatting

The content discusses the role of follicular helper-like (Tfh) and peripheral helper-like (Tph) T cells in the development of autoimmune disease in human immune system (HIS) mice.

Key highlights:

HIS mice with a native mouse thymus (Mu/Hu) develop autoimmune disease more rapidly than those with a human thymus graft (Hu/Hu).
Mu/Hu mice have higher frequencies of circulating Tfh-like cells compared to Hu/Hu mice, which is associated with increased serum IgG levels.
Tfh-like and Tph-like cells from Hu/Hu mice have greater capacity to help B cell differentiation and antibody production compared to those from Mu/Hu mice.
Depletion of B cells does not prevent or delay the development of autoimmune disease in HIS mice, suggesting a minor role for antibodies.
Adoptive transfer of Tfh-like and Tph-like cells from Hu/Hu mice, but not Mu/Hu mice, can induce autoimmune disease and autoimmunity-associated B cell phenotypes in recipient mice containing human antigen-presenting cells (APCs) without T cells.
T cells from Hu/Hu mice expand and induce disease more rapidly than those from Mu/Hu mice, implicating HLA-restricted T cell-APC interactions in this process.

The observations provide a platform for further dissection of human autoimmune disease mechanisms and therapies, as Tfh, Tph, autoantibodies, and lymphopenia-induced proliferation have all been implicated in various forms of human autoimmune disease.

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biorxiv.org

Statistieken

Serum IgG levels were significantly greater in Mu/Hu mice compared to Hu/Hu mice.
Serum from Mu/Hu and Hu/Hu mice contained IgM antibodies reactive to multiple murine tissues, and several Mu/Hu mice also contained IgG antibodies with broad reactivity to multiple murine tissues.
The sum of IgM concentrations reacting to dsDNA, insulin and LPS was >100% of total serum IgM in 3 Mu/Hu mice, consistent with polyreactivity of individual B cells in these mice.

Citaten

"Tfh-like cells were more prominent in HIS mice with a mouse thymus, in which the highest levels of IgG were detected in plasma, compared to those with a human thymus."
"While circulating IgG and IgM antibodies were autoreactive to multiple mouse antigens, in vivo depletion of B cells and antibodies did not delay the development of autoimmune disease."
"T cells from mice with a human thymus expanded and induced disease more rapidly than those originating in a murine thymus, implicating HLA-restricted T cell-APC interactions in this process."

Belangrijkste Inzichten Gedestilleerd Uit

Follicular helper- and peripheral helper-like T cells drive autoimmune disease in human immune system mice

by Vecchione,A.... om www.biorxiv.org 05-05-2024

https://www.biorxiv.org/content/10.1101/2024.05.02.591692v1

Diepere vragen

How do the differences in thymic selection between Mu/Hu and Hu/Hu mice impact the functional properties and pathogenicity of Tfh-like and Tph-like cells beyond their ability to help B cells?

The differences in thymic selection between Mu/Hu and Hu/Hu mice have significant implications for the functional properties and pathogenicity of Tfh-like and Tph-like cells. In Mu/Hu mice, where human T cells develop in the native murine thymus, there is a lack of normal negative selection for self-antigens due to the absence of a normal thymic structure, including a paucity of medullary epithelial cells. This results in the generation of T cells that are not tolerized to murine antigens, leading to their recognition of murine peptides presented on human APCs. These T cells may react with human APCs loaded with murine antigens, including human B cells, in a manner resembling an alloresponse, potentially activating B cells and inducing polyclonal class-switched antibody responses, including autoantibodies.
On the other hand, in Hu/Hu mice, where T cells develop in a human fetal thymus graft, there is normal negative selection for self-antigens, resulting in T cells that are tolerized to tissue-restricted murine antigens presented on human APCs. This leads to more effective interactions between T cells and autologous human APCs and B cells, optimizing T cell expansion and B cell differentiation. The Tfh-like and Tph-like cells generated in an autologous human thymus graft interact more effectively with peripheral B cells and other APCs, likely due to positive selection on the same HLA molecules as those in the peripheral APCs, resulting in enhanced T cell expansion, increased CD11c expression on B cells, and eventually disease development.

How do the potential mechanisms by which B cell depletion accelerates disease development in HIS mice, if antibodies are not the primary drivers?

The potential mechanisms by which B cell depletion accelerates disease development in HIS mice, even when antibodies are not the primary drivers, can be attributed to the regulatory role of B cells in autoimmune disease. While B cells and antibodies may not be required for disease development, B cells can play a role in regulating immune responses and maintaining tolerance. In the absence of B cells, there may be a dysregulation of immune responses, leading to unchecked activation of T cells and other effector cells.
B cells have been shown to have regulatory functions in autoimmune diseases, including the production of regulatory cytokines and the modulation of T cell responses. By depleting B cells, the regulatory mechanisms that normally suppress autoimmune responses may be disrupted, leading to increased activation of autoreactive T cells and other effector cells. This dysregulation can accelerate the development of autoimmune disease in HIS mice, even in the absence of a direct role for antibodies in driving the pathology.

What are the specific murine antigens recognized by the autoreactive T cells that develop in the Mu/Hu mice, and how do they contribute to the induction of autoimmunity when presented on human APCs?

The autoreactive T cells that develop in the Mu/Hu mice recognize specific murine antigens that are presented on human APCs, contributing to the induction of autoimmunity in these mice. The lack of tolerance to murine antigens in the primary Mu/Hu mice reflects the absence of normal negative selection in the native murine thymus, resulting in the generation of T cells that are not tolerized to murine antigens. These T cells may recognize tissue-restricted murine antigens that are presented on human APCs, leading to their activation and the initiation of autoimmune responses.
The specific murine antigens recognized by the autoreactive T cells in Mu/Hu mice may include peptides derived from tissue-specific proteins or antigens that are normally expressed by murine cells. When these murine antigens are presented on human APCs, the autoreactive T cells can interact with the HLA molecules on the APCs, leading to T cell activation and the production of pro-inflammatory cytokines. This activation of T cells by murine antigens presented on human APCs can trigger an autoimmune response, resulting in tissue damage and the development of autoimmune disease in the Mu/Hu mice.