TIGIT-Fc fusion protein alleviates murine lupus nephritis through the regulation of SPI-B-PAX5-XBP1 axis-mediated B-cell differentiation

Zhao, Junpeng; Li, Liming; Feng, Xi‐Qiao; Gao, Changxing; Gao, Lijie; Zhan, Yijing; Wang, Zijun; Zhao, Ming; Yin, Hongen; Lu, Qianjin

doi:10.1016/j.jaut.2023.103087

Cited by 5 publications

(8 citation statements)

References 33 publications

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“…Additionally, the TIGIT-Ig group exhibited a diminished frequency of Th1, Tfh, and various B cell subtypes, including plasma cells, plasmablasts, and germinal center B cells, compared to the negative control group. 9 Notably, this investigation also revealed a heightened frequency of spleen Tregs of the mice after the treatment of TIGIT-Fc fusion protein. This observation contributed to the discovery of a novel mechanism by which the activation of TIGIT signaling may modulate the differentiation of B cells.…”

Section: Tigit-based Therapy In Slementioning

confidence: 56%

“…13 Subtypes of B cells, including memory B cells, plasma cells, and Bregs, definitively exhibit TIGIT expression. 9,14,15 A mounting body of evidence underscores the extension of TIGIT expression to various innate immune cells, encompassing T cells, innate lymphoid cells, invariant natural killer T cells, and macrophages, instigating heightened immunosuppressive responses. [16][17][18] This revelation bears substantial implications for comprehending the regulatory role of TIGIT in immune function, transcending its established functions in T and NK cells.…”

Section: Expressionmentioning

confidence: 99%

“…This effect is mediated via the effect of the SPI-B-PAX5-XBP1 signaling. 9 In summary, TIGIT primarily exerts immunosuppressive functions on various immune cells through a range of mechanisms, contributing to the regulation of immune responses (Figure 2). TIGIT-based treatment shows promise as a potential approach to managing autoimmune disorders.…”

Section: Mechanism Of Immune Regulationmentioning

confidence: 99%

“…Specifically, it operates via the SPI-B-PAX5-XBP1 signaling, ultimately leading to a decrease in the production of antibodies. 9 Therefore, TIGIT can be an emerging IC target for immunotherapy in SLE.…”

Section: Tigit-based Therapy In Slementioning

confidence: 99%

“…6,7 Several therapeutic approaches, including CD155 protein, agonistic anti-TIGIT monoclonal antibody, and TIGIT fusion protein, have been deployed in the treatment of autoimmune disorders, with a particular focus on SLE. [8][9][10] To date, there is a lack of comprehensive reviews addressing TIGIT as a potential therapeutic target for SLE. In this comprehensive review, we offer an in-depth exploration of the attributes of TIGIT within the context of autoimmunity, while also deliberating on its potential as a promising therapeutic target in the management of SLE.…”

Section: Introductionmentioning

confidence: 99%

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T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as a promising immune checkpoint target for the treatment of SLE

Zhao,

Li,

Feng

et al. 2024

Lupus

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Immune checkpoints (ICs) play a pivotal role in orchestrating immune regulation, crucial for the maintenance of immune tolerance and prevention of autoimmune diseases. One noteworthy example among these immune regulators is T cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT). The TIGIT pathway’s inhibition or the absence of TIGIT has been linked to the hyperactivation and excessive proliferation of T cells, rendering individuals more susceptible to autoimmune diseases and exacerbating inflammatory responses. Conversely, the activation of TIGIT has exhibited promising outcomes in ameliorating autoimmune disorders, as observed in murine models of systemic lupus erythematosus (SLE). Consequently, a judicious exploration of the co-inhibitory axis appears warranted for the effective management of pathogenic immune responses in SLE. In light of compelling evidence, this review undertakes a comprehensive examination of TIGIT’s characteristics within the context of autoimmunity, offering insights into its potential as a therapeutic target for SLE.

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Section: Tigit-based Therapy In Slementioning

confidence: 56%

Section: Expressionmentioning

confidence: 99%

Section: Mechanism Of Immune Regulationmentioning

confidence: 99%

Section: Tigit-based Therapy In Slementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as a promising immune checkpoint target for the treatment of SLE

Zhao,

Li,

Feng

et al. 2024

Lupus

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Landscape of gut mucosal immune cells showed gap of follicular or memory B cells into plasma cells in immunological non‐responders

Wang,

Zhen,

Guo

et al. 2024

Clinical & Translational Med

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BackgroundThe gut is an important site for human immunodeficiency virus (HIV) infection and immune responses. The role of gut mucosal immune cells in immune restoration in patients infected with HIV undergoing antiretroviral therapy remains unclear.MethodsIleocytes, including 54 475 immune cells, were obtained from colonoscopic biopsies of five HIV‐negative controls, nine immunological responders (IRs), and three immunological non‐responders (INRs) and were analyzed using single‐cell RNA sequencing. Immunohistochemical assays were performed for validation. The 16S rRNA gene was amplified using PCR in faecal samples to analyze faecal microbiota. Flow cytometry was used to analyze CD4+ T‐cell counts and the activation of T cells.ResultsThis study presents a global transcriptomic profile of the gut mucosal immune cells in patients infected with HIV. Compared with the IRs, the INRs exhibited a lower proportion of gut plasma cells, especially the IGKC+IgA+ plasma cell subpopulation. IGKC+IgA+ plasma cells were negatively associated with enriched f. Prevotellaceae the INRs and negatively correlated with the overactivation of T cells, but they were positively correlated with CD4+ T‐cell counts. The INRs exhibited a higher proportion of B cells than the IRs. Follicular and memory B cells were significantly higher in the INRs. Reduced potential was observed in the differentiation of follicular or memory B cells into gut plasma cells in INRs. In addition, the receptor‐ligand pairs CD74_MIF and CD74_COPA of memory B/ follicular helper T cells were significantly reduced in the INRs, which may hinder the differentiation of memory and follicular B cells into plasma cells.ConclusionsOur study shows that plasma cells are dysregulated in INRs and provides an extensive resource for deciphering the immune pathogenesis of HIV in INRs.Key points An investigation was carried out at the single‐cell‐level to analyze gut mucosal immune cells alterations in PLWH after ART. B cells were significantly increased and plasma cells were significantly decreased in the INRs compared to the IRs and NCs. There are gaps in the transition from gut follicular or memory B cellsinto plasma cells in INRs.

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Blockade of OX40/OX40L signaling using anti‐OX40L alleviates murine lupus nephritis

Zhao,

Li,

Feng

et al. 2024

Eur J Immunol

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Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti‐OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti‐OX40L on immunosuppression in keyhole limpet hemocyanin‐immunized C57BL/6J mice. In vitro treatment of anti‐OX40L in CD4+ T and B220+ B cells was used to explore the role of OX40L in the pathogenesis of SLE. Anti‐OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti‐dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T‐follicular helper cells (Tfh). In keyhole limpet hemocyanin‐immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti‐OX40L group. Anti‐OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti‐OX40L downregulated CD4+ T‐cell differentiation into Th1 and Tfh cells and upregulated CD4+ T‐cell differentiation into regulatory T cells in vitro. Furthermore, anti‐OX40L inhibited toll‐like receptor 7‐mediated differentiation of antibody‐secreting cells and antibody production through the regulation of the SPIB‐BLIMP1‐XBP1 axis in B cells. These results suggest that OX40L is a promising therapeutic target for SLE.

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TIGIT-Fc fusion protein alleviates murine lupus nephritis through the regulation of SPI-B-PAX5-XBP1 axis-mediated B-cell differentiation

Cited by 5 publications

References 33 publications

T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as a promising immune checkpoint target for the treatment of SLE

T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as a promising immune checkpoint target for the treatment of SLE

Landscape of gut mucosal immune cells showed gap of follicular or memory B cells into plasma cells in immunological non‐responders

Blockade of OX40/OX40L signaling using anti‐OX40L alleviates murine lupus nephritis

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