High‐dimensional single‐cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis

Fuchs, Sebastian; Sawas, Nadia; Staedler, Nicolas; Schubert, David; D’Andrea, Annalisa; Zeiser, Robert; Piali, Luca; Hrúz, Petr; Frei, Andreas P.

doi:10.1002/eji.201847862

Cited by 12 publications

(10 citation statements)

References 77 publications

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“…Yu et al (16) reported that IL-21 could regulate the proliferation and response of TFH cells in the colitis microenvironment. Sebastian Fuchs et al found that the frequency of CXCR5 + PD1 + TFH cells in peripheral blood was significantly increased in 5-ASA treated UC patients (37). Decreased circulating FoxP3 + CXCR5 + TFR cells and increased FoxP3 − CXCR5 + TFH cells in UC patients were once reported (17), but their study lacked detailed clinical staging studies.…”

Section: Discussionmentioning

confidence: 99%

The Imbalance of Circulating Follicular Helper T Cells and Follicular Regulatory T Cells Is Associated With Disease Activity in Patients With Ulcerative Colitis

Long

Xia

et al. 2020

Front. Immunol.

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the colon and rectum, in which the abnormality of B cells is involved in both its pathogenesis and progression. Follicular helper T cells (TFH) play an important role in assisting the immune function of human B cells in germinal centers, and follicular regulatory T cells (TFR) have the function of inhibiting TFH and germinal center B cell responses. The significance of circulating TFH and TFR in ulcerative colitis (UC) remains unclear. We analyzed peripheral blood of active and stable remission UC patients and found that circulating TFR was significantly decreased while TFH was increased in active UC patients. As to TFH subsets, TFH2 was elevated while TFH17 was decreased in active UC, with IL-4/IL-17A secretion enhanced. Helios + and CD45RA − FoxP3 high TFR cells were decreased while CD226 + and CD45RA + FoxP3 int TFR cells were increased in active UC patients. The levels of new memory B cells, plasmablasts and serum IgG were significantly increased in active UC patients, and were positively correlated with TFH and TFH2, and negatively correlated with TFR. Serum CRP and Mayo Clinic scores were positively correlated with TFH and TFH2 but negatively correlated with TFR. Serum IL-12 and IL-21 were up-regulated while IL-10 was down-regulated in active UC. To conclude, an imbalance of circulating TFH and TFR cells is associated with disease activity in UC patients. Our results suggest a new mechanism for TFH and TFR imbalance in the pathogenesis of UC, providing a new perspective for theoretical research and therapeutic strategies for UC.

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Section: Discussionmentioning

confidence: 99%

The Imbalance of Circulating Follicular Helper T Cells and Follicular Regulatory T Cells Is Associated With Disease Activity in Patients With Ulcerative Colitis

Long

Xia

et al. 2020

Front. Immunol.

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“…Sample preparation was performed as described previously ( Fuchs et al, 2019 ) with antibodies listed in Table S4 . A Helios mass cytometry instrument (Fluidigm) was used for sample acquisition.…”

Section: Methodsmentioning

confidence: 99%

A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS

Maccari

Fuchs

Küry

et al. 2020

Journal of Experimental Medicine

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The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET− expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.

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“…In UC, infiltration of immune cells into the intestinal mucosa could cause chronic inflammation. Some subtle but significant changes in immune cell frequencies and immune checkpoint expression were observed in patients with UC compared to HCs from a high-dimensional single-cell proteomics data by mass cytometry (94). The results also showed the increased expression of TIM-3 and TIGIT on NK cells, increased expression of CD155, PD-L1 and VISTA on monocytes, and decreased expression of TIGIT on CD4 + T cells (94).…”

Section: Inflammatory Bowel Diseasesmentioning

confidence: 91%

“…NK cells are present in the intestinal mucosa under both the healthy and diseased conditions. Recently, a reduced number of peripheral NK cells was observed in UC patients (94). In UC, infiltration of immune cells into the intestinal mucosa could cause chronic inflammation.…”

Section: Inflammatory Bowel Diseasesmentioning

confidence: 99%

TIGIT as a Promising Therapeutic Target in Autoimmune Diseases

Yue

Gao

et al. 2022

Front. Immunol.

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Co-inhibitory receptors (IRs) are molecules that protect host against autoimmune reactions and maintain peripheral self-tolerance, playing an essential role in maintaining immune homeostasis. In view of the substantial clinical progresses of negative immune checkpoint blockade in cancer treatment, the role of IRs in autoimmune diseases is also obvious. Several advances highlighted the substantial impacts of T cell immunoglobulin and ITIM domain (TIGIT), a novel IR, in autoimmunity. Blockade of TIGIT pathway exacerbates multiple autoimmune diseases, whereas enhancement of TIGIT function has been shown to alleviate autoimmune settings in mice. These data suggested that TIGIT pathway can be manipulated to achieve durable tolerance to treat autoimmune disorders. In this review, we provide an overview of characteristics of TIGIT and its role in autoimmunity. We then discuss recent approaches and future directions to leverage our knowledge of TIGIT as therapeutic target in autoimmune diseases.

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High‐dimensional single‐cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis

Cited by 12 publications

References 77 publications

The Imbalance of Circulating Follicular Helper T Cells and Follicular Regulatory T Cells Is Associated With Disease Activity in Patients With Ulcerative Colitis

The Imbalance of Circulating Follicular Helper T Cells and Follicular Regulatory T Cells Is Associated With Disease Activity in Patients With Ulcerative Colitis

A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS

TIGIT as a Promising Therapeutic Target in Autoimmune Diseases

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