Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA196942 | ENA |
REPOSITORIES: ENA
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Project description:Peptide immunotherapy aims to specifically restore tolerance to the administered self-antigen and prevent autoimmunity without the perturbation of normal immune function. We have developed a dose escalation protocol for subcutaneous delivery of the MHC II-restricted myelin basic protein peptide analogue Ac1-9[4Y] to T cell receptor transgenic (Tg4) mice. Dose escalation allows safe administration of high doses of peptide, which effectively induces antigen-specific tolerance and suppresses the development of experimental autoimmune encephalomyelitis, a model for the human condition multiple sclerosis. CD4+ T cells isolated from treated mice are anergic and suppressive in vitro and respond to stimulation by secretion of the immunoregulatory cytokine IL-10. To understand the molecular changes occurring throughout the course of dose-escalation immunotherapy, we undertook microarray analysis of CD4+ T cells at different the stages of treatment, using Tg4 Rag-1 deficient mice, which lack naturally occurring regulatory T cells and have a monoclonal CD4+ T cell population
2014-07-14 | GSE46036 | GEO
Project description:During infections, Foxp3+ regulatory T (Treg) cells must control autoreactive conventional T (Tconv) cell responses against self-peptide antigens while permitting those against pathogen-derived “nonself” peptides. We sought to define the basis of this selectivity using mice in which Tregs reactive to a single prostate-specific self-peptide/MHC (self-pMHC) antigen, termed "C4", were selectively depleted ("C4ΔTEC" mice). We demonstrated that Tregs reactive to the C4 peptide were dispensable for the control of Tconv cells of matched antigen specificity at homeostasis but were required to control such Tconv cells and prevent fulminant prostatic autoimmunity following infection with the pathogen L monocytogenes engineered to express the C4 peptide ("Lm[C4]"). We performed the experiment outlined here to understand how the absence of C4-specific Treg cells in C4ΔTEC mice changes the phenotypic state of the C4-specific Tconv cells following Lm[C4] infection to drive autoimmunity. We found that C4-specific Tconv cells adopted preferential and differential cell states in both C4ΔTEC mice and wild-type mice that have C4-specific Treg cells. Specifically, gene expesion data revealed that C4-specific Tconv cells in wild-type mice preferentially adopted a non-proliferating effector state, while C4-specific Tconv in C4ΔTEC mice appeared as proliferating effector cells and proliferating central-memory cells.
2025-04-23 | GSE235974 | GEO
Project description:CD8+ T cells play a critical role in immune tolerance maintainnance after immune activation. It is known to function through targeting activated CD4+ T cells, in both Qa-1- and MHC-Ia-restricted9 manner. However, the exact nature of this targeting process, i.e., the specific peptides and the corresponding reactive CD8 TCRs, remains unknown. In this study, we identified the self-peptides on activated CD4+ T cells that could mediate the CD8+ T cells immunosuppressive activity. By cloning the corresponding CD8 TCRs and the generation of TCR transgenic mice , we were able to validate the immunosuppressive function of CD8+ T cells carrying the self-reactive TCRs both in vitro and in vivo. The therapeutic potential of peptide vaccination and CD8+ T cell transfer were confirmed in a mouse EAE model. This study suggest that self-tolerance can be maintained by self-reactive CD8+ T cells recognizing self-antigenic peptides through specific TCRs, thus redefine the nature of CD8+ regulatory T cells as self-reactive CD8+ T cells.
2025-08-30 | GSE276227 | GEO
Project description:CD8+ T cells play a critical role in immune tolerance maintainnance after immune activation. It is known to function through targeting activated CD4+ T cells, in both Qa-1- and MHC-Ia-restricted9 manner. However, the exact nature of this targeting process, i.e., the specific peptides and the corresponding reactive CD8 TCRs, remains unknown. In this study, we identified the self-peptides on activated CD4+ T cells that could mediate the CD8+ T cells immunosuppressive activity. By cloning the corresponding CD8 TCRs and the generation of TCR transgenic mice , we were able to validate the immunosuppressive function of CD8+ T cells carrying the self-reactive TCRs both in vitro and in vivo. The therapeutic potential of peptide vaccination and CD8+ T cell transfer were confirmed in a mouse EAE model. This study suggest that self-tolerance can be maintained by self-reactive CD8+ T cells recognizing self-antigenic peptides through specific TCRs, thus redefine the nature of CD8+ regulatory T cells as self-reactive CD8+ T cells.
2025-09-01 | GSE276189 | GEO
Project description:Antigen-specific regulation of autoimmune disease is a major clinical research goal. In seropositive rheumatoid arthritis (RA), T cells help to autoreactive B cells matures the citrullinated antigen-specific immune response, generating RA-specific V-domain glycosylated anti-citrullinated (Cit) protein antibodies (VDG ACPA) before arthritis onset. Repeated low or escalating antigen doses administered under “sub-immunogenic” conditions generally favors tolerance. The aims of this study were to explore the safety, pharmacokinetics, immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273 (CII) and NF-KB inhibitor 1,25-dihydroxycholecalciferol (calcitriol)
2022-12-05 | GSE208161 | GEO
Project description:Self-tolerance maintained by self-reactive CD8+ T cells
| PRJNA1156020 | ENA
Project description:Self-tolerance maintained by self-reactive CD8+ T cells
| PRJNA1155661 | ENA
Project description:Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.
2024-01-26 | PXD044740 | Pride