Dataset Information

Soluble CD83 Regulates Dendritic Cell-T Cell Immunological Synapse Formation by Disrupting Rab1a-Mediated F-Actin Rearrangement.

ABSTRACT: Dendritic cell-T cell (DC-T) contacts play an important role in T cell activation, clone generation, and development. Regulating the cytoskeletal protein rearrangement of DCs can modulate DC-T contact and affect T cell activation. However, inhibitory factors on cytoskeletal regulation in DCs remain poorly known. We showed that a soluble form of CD83 (sCD83) inhibited T cell activation by decreasing DC-T contact and synapse formation between DC and T cells. This negative effect of sCD83 on DCs was mediated by disruption of F-actin rearrangements, leading to alter expression and localization of major histocompatibility complex class II (MHC-II) and immunological synapse formation between DC and T cells. Furthermore, sCD83 was found to decrease GTP-binding activity of Rab1a, which further decreased colocalization and expression of LRRK2 and F-actin rearrangements in DCs, leading to the loss of MHC-II at DC-T synapses and reduced DC-T synapse formation. Further, sCD83-treated DCs alleviated symptoms of experimental autoimmune uveitis in mice and decreased the number of T cells in the eyes and lymph nodes of these animals. Our findings demonstrate a novel signaling pathway of sCD83 on regulating DC-T contact, which may be harnessed to develop new immunosuppressive therapeutics for autoimmune disease.

SUBMITTER: Lin W

PROVIDER: S-EPMC7874230 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Soluble CD83 Regulates Dendritic Cell-T Cell Immunological Synapse Formation by Disrupting Rab1a-Mediated F-Actin Rearrangement.

Lin Wei W Zhou Shuping S Feng Meng M Yu Yong Y Su Qinghong Q Li Xiaofan X

Frontiers in cell and developmental biology 20210122

Dendritic cell-T cell (DC-T) contacts play an important role in T cell activation, clone generation, and development. Regulating the cytoskeletal protein rearrangement of DCs can modulate DC-T contact and affect T cell activation. However, inhibitory factors on cytoskeletal regulation in DCs remain poorly known. We showed that a soluble form of CD83 (sCD83) inhibited T cell activation by decreasing DC-T contact and synapse formation between DC and T cells. This negative effect of sCD83 on DCs wa ...[more]

PMID: 33585445

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Project description:Dendritic cells (DCs) are the professional antigen presenting cells, which play important roles in regulating the immune response and tolerance. In mammals, CD83 is considered as a maturation marker for DCs, which is a type I membrane glycoprotein. In this research, the gene sequence of the CD83 in Paralichthys olivaceus was obtained on NCBI, the sequence characteristics were studied and CD83 was detected in the head kidney, spleen, gut, gill, liver and muscle, with lower expression in the liver and muscle and higher expression in the head kidney and spleen. And then the CD83 recombinant protein was expressed and the specific antibodies (Abs) were prepared, transiently expressed CD83 eukaryotic proteins could be identified by western blot and indirect immunofluorescence. Then single cell suspensions of head kidney were obtained and DCs were collected by density gradient centrifugation after 7 days of cultivation. Giemsa staining revealed that the nuclei were kidney and dumbbell shaped, and the cell surfaces had dendritic or pseudopod-like protrusions. In addition, the DCs could phagocytose fluorescent microspheres, and the phagocytosis rate was 79.27±1.01%. After incubation with allogeneic lymphocytes, it was found that the lymphocytes clustered and proliferated significantly with the ratio ranging from 39.0% to 59.8% in a dose-dependent manner, which proved that the DCs could elicit mixed lymphocyte responses. After LPS immunization in vivo, the relative expression of CD83 in the head kidney and spleen showed a trend of increasing and then decreasing, peaking at 6 h. Meanwhile, the expression of CD83, MHC II, CD80/86 and CD40 were significantly up-regulated in DCs after stimulated with LPS for 24 h in vitro. And then IIF revealed that CD83+ cells could be detected in the LPS-stimulated group using CD83 Abs, while no positive signal was detected in the control group, which suggested that CD83 protein may be considered as a specific marker for the maturation of DCs in teleost.

Project description:Full T cell activation requires coordination of signals from multiple receptor-ligand pairs that interact in parallel at a specialized cell-cell contact site termed the immunological synapse (IS). Signaling at the IS is intimately associated with actin dynamics; T cell receptor (TCR) engagement induces centripetal flow of the T cell actin network, which in turn enhances the function of ligand-bound integrins by promoting conformational change. Here, we have investigated the effects of integrin engagement on actin flow, and on associated signaling events downstream of the TCR. We show that integrin engagement significantly decelerates centripetal flow of the actin network. In primary CD4+ T cells, engagement of either LFA-1 or VLA-4 by their respective ligands ICAM-1 and VCAM-1 slows actin flow. Slowing is greatest when T cells interact with low mobility integrin ligands, supporting a predominately drag-based mechanism. Using integrin ligands presented on patterned surfaces, we demonstrate that the effects of localized integrin engagement are distributed across the actin network, and that focal adhesion proteins, such as talin, vinculin, and paxillin, are recruited to sites of integrin engagement. Further analysis shows that talin and vinculin are interdependent upon one another for recruitment, and that ongoing actin flow is required. Suppression of vinculin or talin partially relieves integrin-dependent slowing of actin flow, indicating that these proteins serve as molecular clutches that couple engaged integrins to the dynamic actin network. Finally, we found that integrin-dependent slowing of actin flow is associated with reduction in tyrosine phosphorylation downstream of the TCR, and that this modulation of TCR signaling depends on expression of talin and vinculin. More generally, we found that integrin-dependent effects on actin retrograde flow were strongly correlated with effects on TCR signaling. Taken together, these studies support a model in which ligand-bound integrins engage the actin cytoskeletal network via talin and vinculin, and tune TCR signaling events by modulating actin dynamics at the IS.

Dataset Information

Soluble CD83 Regulates Dendritic Cell-T Cell Immunological Synapse Formation by Disrupting Rab1a-Mediated F-Actin Rearrangement.

Publications

Soluble CD83 Regulates Dendritic Cell-T Cell Immunological Synapse Formation by Disrupting Rab1a-Mediated F-Actin Rearrangement.

Similar Datasets

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