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T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.

ABSTRACT: The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non-exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities.

SUBMITTER: McKinney EF

PROVIDER: S-EPMC4623162 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.

McKinney Eoin F EF Lee James C JC Jayne David R W DR Lyons Paul A PA Smith Kenneth G C KG

Nature 20150629 7562

The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chron ...[more]

PMID: 26123020

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Project description:Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Clinicaltrials.gov NCT00623610.

Project description:Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the 'exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such as programmed cell death-1 (PD-1), lymphocyte activation gene-3, cytotoxic T lymphocyte-associated antigen-4 and CD244. As both CD4(+) and CD8(+) T cells participate in the immune responses against chronic hepatitis virus through distinct manners, compelling evidences have been proposed, which restore the anti-viral function of these exhausted T cells by blocking those inhibitory receptors with its ligand and will pave the way for the development of more effective immunotherapeutic and prophylactic strategies for the treatment of chronic infectious diseases. A large number of studies have stated the essentiality of T-cell exhaustion in virus-infected diseases, such as LCMV, hepatitis C virus (HCV), human immunodeficiency virus infections and cancers. Besides, the functional restoration of HCV- and HIV-specific CD8(+) T cells by PD-1 blockade has already been repeatedly verified, and also for the immunological control of tumors in humans, blocking the PD-1 pathway could be a major immunotherapeutic strategy. Although the specific molecular pathways of T-cell exhaustion remain ambiguous, several transcriptional pathways have been implicated in T-cell exhaustion recently; among them Blimp-1, T-bet and NFAT2 were able to regulate exhausted T cells during chronic viral infection, suggesting a distinct lineage fate for this sub-population of T cells. This paper summarizes the current literature relevant to T-cell exhaustion in patients with HBV-related chronic hepatitis, the options for identifying new potential therapeutic targets to treat HBV infection and highlights priorities for further study.

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T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.

Publications

T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.

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