Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients
- Institut Pasteur, France
- University Pierre et Marie Curie, France
- Albert-Ludwigs-Universität, Germany
- Assistance publique - hôpitaux de Paris, France
- The Netherlands Cancer Institute, Netherlands
- Lunds University, Sweden
- Assistance publique - Hôpitaux de Paris, France
- Université Paris Descartes, France
- Assistance Publique - Hôpitaux de Paris, France
- Albert-Ludwigs-Universität Freiburg, Germany
Abstract
Chronic infection perturbs immune homeostasis. While prior studies have reported dysregulation of effector and memory cells, little is known about the effects on naïve T cell populations. We performed a cross-sectional study of chronic hepatitis C (cHCV) patients using tetramer-associated magnetic enrichment to study antigen-specific inexperienced CD8+ T cells (i.e., tumor or unrelated virus-specific populations in tumor-free and sero-negative individuals). cHCV showed normal precursor frequencies, but increased proportions of memory-phenotype inexperienced cells, as compared to healthy donors or cured HCV patients. These observations could be explained by low surface expression of CD5, a negative regulator of TCR signaling. Accordingly, we demonstrated TCR hyperactivation and generation of potent CD8+ T cell responses from the altered T cell repertoire of cHCV patients. In sum, we provide the first evidence that naïve CD8+ T cells are dysregulated during cHCV infection, and establish a new mechanism of immune perturbation secondary to chronic infection.
Article and author information
Author details
Reviewing Editor
- Rafi Ahmed, Emory, United States
Ethics
Human subjects: 29 cHCV, 37 SVR, and 18 cHBV patients were included (Table 1). All subjects were followed in the Liver Unit of H�pital Cochin (Paris, France) or the Department of Internal Medicine II (Freiburg, Germany). French samples were obtained as part of study protocol C11-33 approved by the INSERM clinical investigation department with ethical approval from the CPP Ile-de-France II, Paris (ClinicalTrials.gov identifier: n{degree sign}NCT01534728). German samples were obtained in the University Hospital Freiburg according to regulations of local ethic committee. Both study protocols conformed to the ethical guidelines of the Declaration of Helsinki, and patients provided informed consent.
Version history
- Received: April 3, 2015
- Accepted: November 12, 2015
- Accepted Manuscript published: November 14, 2015 (version 1)
- Version of Record published: January 19, 2016 (version 2)
Copyright
© 2015, Alanio et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Bystander hyperactivation of preimmune CD8+ T cells in chronic HCV patients
eLife 4:e07916.
https://doi.org/10.7554/eLife.07916
Further reading
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- Evolutionary Biology
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CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
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