Cytomegalovirus restricts ICOSL expression on antigen-presenting cells disabling T cell co-stimulation and contributing to immune evasion

Abstract

Viral infections are controlled, and very often cleared, by activated T lymphocytes. The inducible co-stimulator (ICOS) mediates its functions by binding to its ligand ICOSL, enhancing T-cell activation and optimal germinal center (GC) formation. Here, we show that ICOSL is heavily downmodulated during infection of antigen-presenting cells by different herpesviruses. We found that, in murine cytomegalovirus (MCMV), the immunoevasin m138/fcr-1 physically interacts with ICOSL, impeding its maturation and promoting its lysosomal degradation. This viral protein counteracts T-cell responses, in an ICOS-dependent manner, and limits virus control during the acute MCMV infection. Additionally, we report that blockade of ICOSL in MCMV-infected mice critically regulates the production of MCMV-specific antibodies due to a reduction of T follicular helper and GC B cells. Altogether, these findings reveal a novel mechanism evolved by MCMV to counteract adaptive immune surveillance, and demonstrates a role of the ICOS:ICOSL axis in the host defense against herpesviruses.

Ferroptosis-Related lncRNA for the Establishment of Novel Prognostic Signature and Therapeutic Response Prediction to Endometrial Carcinoma

“…Conversely, T cell costimulation was more prevalent in the low-risk group. This could be because cytomegalovirus in the high-risk group inhibits ICOSL transcription on antigen-presenting cells, inhibiting T lymphocyte costimulation, thereby resulting in immunological resistance [ 49 ].…”

Dual regulation effect and mechanism of human myeloid‐derived suppressor cells on anticolorectal cancer cells activity of Vγ9Vδ2 T cells

“…Activated T cells express ICOS on their surface, which enhances the ability of T cells to secrete cytokines after binding to ICOSL on the surface of cells, such as B cells, DC, and macrophages 23,24 . Our results show that activated Vγ9Vδ2 T cells also express ICOS on its surface (Figure 7B,E) and ICOSL on the MDSC surface of the same individual (Figure 7C,F), but the result of neutralizing ICOSL is disappointed (Figure 7J–L).…”

“…However, the addition of immune checkpoint mixed neutralizing antibodies has no significant effect on the ability of MDSC to downregulate NKG2D expression and upregulate the produce of CD107a, IFN-γ, perforin, and Granzyme B in Vγ9Vδ2 T cells (Figures1F, 2-4B-D, and 5B). This further confirms that the effect of MDSC in downregulating NKG2D in Vγ9Vδ2 T cells is only related to its membrane-type TGF-β, and confirms that MDSC has the ability to up-regulate the synthesis and secretion of IFN-γ, perforin, and Granzyme B by Vγ9Vδ2 T cells.Activated T cells express ICOS on their surface, which enhances the ability of T cells to secrete cytokines after binding to ICOSL on the surface of cells, such as B cells, DC, and macrophages 23,24. Our results show that activated Vγ9Vδ2 T cells also express ICOS on its surface (Figure7B,E) and ICOSL on the MDSC surface of the same individual (Figure7C,F), but the result of neutralizing ICOSL is disappointed (Figure7J-L).…”

“…It had been found that ICOS was mainly expressed by activated T cells, which bind to ICOSL expressed by B cells, DCs, and macrophages, and then enhance the formation of germinal centers and cytokine secretion by T cells 23,24 …”

Immune-Related LncRNAs Affect the Prognosis of Osteosarcoma, Which Are Related to the Tumor Immune Microenvironment

“…Low expression of MHC-II molecules can also lead to the occurrence of immune escape due to the inability to effectively activate T cells (Zhi et al, 2021). In addition, the activation of T cells also requires the participation of costimulatory molecules (Angulo et al, 2021). We found that MHC-I molecules, MHC-II molecules, and costimulatory molecules, which are associated with endogenous immune escape, were all low expressed in the high-risk group.…”