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      Expression of TIGIT in splenic and circulatory T cells from mice acutely infected with Toxoplasma gondii Translated title: Expression de TIGIT dans les cellules T spléniques et circulatoires de souris lourdement infectées par Toxoplasma gondii

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      EDP Sciences

      Toxoplasma gondii, T cells, TIGIT, CD226

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          The surface protein TIGIT (T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain) has been characterized as an important regulator of cell-mediated immune responses in various infections. However, TIGIT expression in immune cells of mice infected with Toxoplasma gondii has not been investigated. Here, we detected TIGIT expression and related phenotypes by flow cytometry and real-time PCR in splenic and circulatory T cells of mice infected with the T. gondii RH strain. We found that the expression of TIGIT on the surface of CD4 + T cells and CD8 + T cells from the spleen and peripheral blood mononuclear cells decreased in the early stage, but increased significantly in the late stage of acute T. gondii infection in mice. Importantly, TIGIT expression was positively correlated with lesions in the murine spleen. In addition, T. gondii-specific TIGIT +T CM cells in the spleen were activated and transformed into TIGIT + T EM cells. Hematoxylin and eosin staining of spleen sections and real-time PCR showed that the severity of splenic lesions was positively correlated with the T. gondii load. This study demonstrates that acute T. gondii infection can regulate the expression of TIGIT in T cells and affect immune cell function.

          Translated abstract

          La protéine de surface TIGIT a été caractérisée comme un régulateur important des réponses immunitaires à médiation cellulaire dans diverses infections. Cependant, l’expression de TIGIT dans les cellules immunitaires de souris infectées par Toxoplasma gondii n’a pas été étudiée. Ici, nous avons détecté l’expression de TIGIT et les phénotypes associés par cytométrie en flux et PCR en temps réel dans les cellules T spléniques et circulatoires de souris infectées par la souche RH de T. gondii. Nous avons constaté que l’expression de TIGIT à la surface des cellules T CD4 + et des cellules T CD8 + de la rate et des cellules mononucléées du sang périphérique diminuait au stade précoce, mais augmentait de manière significative au stade avancé de l’infection aiguë à T. gondii chez la souris. Surtout, l’expression de TIGIT était positivement corrélée avec les lésions de la rate de la souris. De plus, des cellules TIGIT +T CM spécifiques de T. gondii dans la rate ont été activées et transformées en cellules T EM. La coloration à l’hématoxyline et à l’éosine (H&E) des coupes de rate et la PCR en temps réel ont montré que la gravité des lésions spléniques était positivement corrélée à la charge en T. gondii. Cette étude démontre qu’une infection aiguë par T. gondii peut réguler à la hausse l’expression de TIGIT dans les cellules T et affecter la fonction des cellules immunitaires.

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          Most cited references 25

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          Identification of PVR (CD155) and Nectin-2 (CD112) as Cell Surface Ligands for the Human DNAM-1 (CD226) Activating Molecule

          Human natural killer (NK) cells express a series of activating receptors and coreceptors that are involved in recognition and killing of target cells. In this study, in an attempt to identify the cellular ligands for such triggering surface molecules, mice were immunized with NK-susceptible target cells. On the basis of a functional screening, four mAbs were selected that induced a partial down-regulation of the NK-mediated cytotoxicity against the immunizing target cells. As revealed by biochemical analysis, three of such mAbs recognized molecules of ∼70 kD. The other mAb reacted with two distinct molecules of ∼65 and 60 kD, respectively. Protein purification followed by tryptic digestion and mass spectra analysis, allowed the identification of the 70 kD and the 65/60 kD molecules as PVR (CD155) and Nectin-2 δ/α (CD112), respectively. PVR-Fc and Nectin-2-Fc soluble hybrid molecules brightly stained COS-7 cells transfected with the DNAM-1 (CD226) construct, thus providing direct evidence that both PVR and Nectin-2 represent specific ligands for the DNAM-1 triggering receptor. Finally, the surface expression of PVR or Nectin-2 in cell transfectants resulted in DNAM-1–dependent enhancement of NK-mediated lysis of these target cells. This lysis was inhibited or even virtually abrogated upon mAb-mediated masking of DNAM-1 (on NK cells) or PVR or Nectin-2 ligands (on cell transfectants).
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            Tolerance and exhaustion: defining mechanisms of T cell dysfunction.

            CD8 T cell activation and differentiation are tightly controlled, and dependent on the context in which naïve T cells encounter antigen, can either result in functional memory or T cell dysfunction, including exhaustion, tolerance, anergy, or senescence. With the identification of phenotypic and functional traits shared in different settings of T cell dysfunction, distinctions between such dysfunctional states have become blurred. Here, we discuss distinct states of CD8 T cell dysfunction, with an emphasis on: (i) T cell tolerance to self-antigens (self-tolerance); (ii) T cell exhaustion during chronic infections; and (iii) tumor-induced T cell dysfunction. We highlight recent findings on cellular and molecular characteristics defining these states, cell-intrinsic regulatory mechanisms that induce and maintain them, and strategies that can lead to their reversal. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              The TIGIT/CD226 axis regulates human T cell function.

              T cell Ig and ITIM domain (TIGIT) is a newly identified receptor expressed on T cells that binds to CD155 on the dendritic cell surface, driving them to a more tolerogenic phenotype. Given that TIGIT contains an ITIM motif in its intracellular domain and considering the potential importance of the TIGIT/CD226 pathway in human autoimmune disease, we investigated the specific role of TIGIT in human CD4(+) T cells. Using an agonistic anti-TIGIT mAb, we demonstrate a direct inhibitory effect on T cell proliferation with a decrease in expression of T-bet, GATA3, IFN regulatory factor 4, and retinoic acid-related orphan receptor c with inhibition of cytokine production, predominantly IFN-γ. Knockdown of TIGIT expression by short hairpin RNA resulted in an increase of both T-bet and IFN-γ mRNA and protein expression with concomitant decrease in IL-10 expression. Increases in IFN-γ with TIGIT knockdown could be overcome by blocking CD226 signaling, indicating that TIGIT exerts immunosuppressive effects by competing with CD226 for the same CD155 ligand. These data demonstrate that TIGIT can inhibit T cell functions by competing with CD226 and can also directly inhibit T cells in a T cell-intrinsic manner. Our results provide evidence for a novel role of this alternative costimulatory pathway in regulating human T cell responses associated with autoimmune disease.

                Author and article information

                EDP Sciences
                25 February 2021
                : 28
                : ( publisher-idID: parasite/2021/01 )
                [1 ] Xinxiang Key Laboratory of Pathogenic Biology, School of Basic Medical Sciences, Xinxiang Medical University Xinxiang 453003 Henan PR China
                [2 ] Second Clinical Medical College, Xinxiang Medical University Xinxiang 453003 Henan PR China
                [3 ] MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University Nanjing 210095 Jiangsu PR China
                Author notes
                parasite200135 10.1051/parasite/2021010
                © S. Wang et al., published by EDP Sciences, 2021

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 25, Pages: 9
                Research Article

                toxoplasma gondii, t cells, tigit, cd226


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