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Dittmer U, Sutter K, Kassiotis G, et al., 2019, Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity, FEMS Microbiology Reviews, Vol: 43, Pages: 435-456, ISSN: 0168-6445
Approximately 4.4% of the human genome is comprised of endogenous retroviral sequences, a record of an evolutionary battle between man and retroviruses. Much of what we know about viral immunity comes from studies using mouse models. Experiments using the Friend virus (FV) model have been particularly informative in defining highly complex anti-retroviral mechanisms of the intrinsic, innate and adaptive arms of immunity. FV studies have unraveled fundamental principles about how the immune system controls both acute and chronic viral infections. They led to a more complete understanding of retroviral immunity that begins with cellular sensing, production of type 1 interferons, and the induction of intrinsic restriction factors. Novel mechanisms have been revealed, which demonstrate that these earliest responses affect not only virus replication, but also subsequent innate and adaptive immunity. This review on FV immunity not only surveys the complex host responses to a retroviral infection from acute infection to chronicity, but also highlights the many feed-back mechanisms that regulate and counter-regulate the various arms of the immune system. In addition, the discovery of molecular mechanisms of immunity in this model have led to therapeutic interventions with implications for HIV cure and vaccine development.
Merkenschlager J, Eksmond U, Danelli L, et al., 2019, MHC class II cell-autonomously regulates self-renewal and differentiation of normal and malignant B cells, Blood, Vol: 133, Pages: 1108-1118, ISSN: 1528-0020
Best known for presenting antigenic peptides to CD4+ T cells, major histocompatibility complex class II (MHC II) also transmits or may modify intracellular signals. Here, we show that MHC II cell-autonomously regulates the balance between self-renewal and differentiation in B-cell precursors, as well as in malignant B cells. Initiation of MHC II expression early during bone marrow B-cell development limited the occupancy of cycling compartments by promoting differentiation, thus regulating the numerical output of B cells. MHC II deficiency preserved stem cell characteristics in developing pro-B cells in vivo, and ectopic MHC II expression accelerated hematopoietic stem cell differentiation in vitro. Moreover, MHC II expression restrained growth of murine B-cell leukemia cell lines in vitro and in vivo, independently of CD4+ T-cell surveillance. Our results highlight an important cell-intrinsic contribution of MHC II expression to establishing the differentiated B-cell phenotype.
Uchil PD, Pi R, Haugh KA, et al., 2019, A protective role for the Lectin CD169/Siglec-1 against a pathogenic murine retrovirus, Cell Host and Microbe, Vol: 25, Pages: 87-100.e10, ISSN: 1931-3128
Lymph- and blood-borne retroviruses exploit CD169/Siglec-1-mediated capture by subcapsular sinus and marginal zone metallophilic macrophages for trans-infection of permissive lymphocytes. However, the impact of CD169-mediated virus capture on retrovirus dissemination and pathogenesis in vivo is unknown. In a murine model of the splenomegaly-inducing retrovirus Friend virus complex (FVC) infection, we find that while CD169 promoted draining lymph node infection, it limited systemic spread to the spleen. At the spleen, CD169-expressing macrophages captured incoming blood-borne retroviruses and limited their spread to the erythroblasts in the red pulp where FVC manifests its pathogenesis. CD169-mediated retroviral capture activated conventional dendritic cells 1 (cDC1s) and promoted cytotoxic CD8+ T cell responses, resulting in efficient clearing of FVC-infected cells. Accordingly, CD169 blockade led to higher viral loads and accelerated death in susceptible mouse strains. Thus, CD169 plays a protective role during FVC pathogenesis by reducing viral dissemination to erythroblasts and eliciting an effective cytotoxic T lymphocyte response via cDC1s.
Kordella C, Kazachenka A, Lamprianidou E, et al., 2018, The Therapeutic Response of Myelodsyplastic Syndromes to Azacytidine Is Independent of Endogenous Retroelement Modulation, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Ottina E, Levy P, Eksmond U, et al., 2018, Restoration of Endogenous Retrovirus Infectivity Impacts Mouse Cancer Models, CANCER IMMUNOLOGY RESEARCH, Vol: 6, Pages: 1292-1300, ISSN: 2326-6066
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- Citations: 14
Danelli L, Donnarumma T, Kassiotis G, 2018, Correlates of follicular helper bias in the CD4 T cell response to a retroviral antigen, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
CD4+ T cell differentiation is influenced by a plethora of intrinsic and extrinsic factors, providing the immune system with the ability to tailor its response according to specific stimuli. Indeed, different classes of pathogens may induce a distinct balance of CD4+ T cell differentiation programmes. Here, we report an uncommonly strong bias toward follicular helper (Tfh) differentiation of CD4+ T cells reactive with a retroviral envelope glycoprotein model antigen, presented in its natural context during retroviral infection. Conversely, the response to the same antigen, presented in different immunization regimens, elicited a response typically balanced between Tfh and T helper 1 cells. Comprehensive quantitation of variables known to influence Tfh differentiation revealed the closest correlation with the strength of T cell receptor (TCR) signaling, leading to PD-1 expression, but not with surface TCR downregulation, irrespective of TCR clonotypic avidity. In contrast, strong TCR signaling leading to TCR downregulation and induction of LAG3 expression in high TCR avidity clonotypes restrained CD4+ T cell commitment and further differentiation. Finally, stunted Th1 differentiation, correlating with limited IL-2 availability in retroviral infection, provided permissive conditions for Tfh development, suggesting that Tfh differentiation is the default program of envelope-reactive CD4+ T cells.
Fontaine M, Vogel I, Van Eycke Y-R, et al., 2018, Regulatory T cells constrain the TCR repertoire of antigen-stimulated conventional CD4 T cells, EMBO JOURNAL, Vol: 37, Pages: 398-412, ISSN: 0261-4189
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- Citations: 7
Attig J, Young GR, Stoye JP, et al., 2017, Physiological and pathological transcriptional activation of endogenous retroelements assessed by RNA-sequencing of B lymphocytes, Frontiers in Microbiology, Vol: 8, ISSN: 1664-302X
In addition to evolutionarily-accrued sequence mutation or deletion, endogenous retroelements (EREs) in eukaryotic genomes are subject to epigenetic silencing, preventing or reducing their transcription, particularly in the germplasm. Nevertheless, transcriptional activation of EREs, including endogenous retroviruses (ERVs) and long interspersed nuclear elements (LINEs), is observed in somatic cells, variably upon cellular differentiation and frequently upon cellular transformation. ERE transcription is modulated during physiological and pathological immune cell activation, as well as in immune cell cancers. However, our understanding of the potential consequences of such modulation remains incomplete, partly due to the relative scarcity of information regarding genome-wide ERE transcriptional patterns in immune cells. Here, we describe a methodology that allows probing RNA-sequencing (RNA-seq) data for genome-wide expression of EREs in murine and human cells. Our analysis of B cells reveals that their transcriptional response during immune activation is dominated by induction of gene transcription, and that EREs respond to a much lesser extent. The transcriptional activity of the majority of EREs is either unaffected or reduced by B cell activation both in mice and humans, albeit LINEs appear considerably more responsive in the latter host. Nevertheless, a small number of highly distinct ERVs are strongly and consistently induced during B cell activation. Importantly, this pattern contrasts starkly with B cell transformation, which exhibits widespread induction of EREs, including ERVs that minimally overlap with those responsive to immune stimulation. The distinctive patterns of ERE induction suggest different underlying mechanisms and will help separate physiological from pathological expression.
Eksmond U, Jenkins B, Merkenschlager J, et al., 2017, Mutation of the putative immunosuppressive domain of the retroviral envelope glycoprotein compromises infectivity, Journal of Virology, Vol: 91, ISSN: 1098-5514
The envelope glycoprotein of diverse endogenous and exogenous retroviruses is considered inherently immunosuppressive. Extensive work mapped the immunosuppressive activity to a highly conserved domain, termed the immunosuppressive domain (ISD), in the transmembrane (TM) subunit of the envelope glycoprotein and identified two naturally polymorphic key residues that afford immunosuppressive activity to distinct envelope glycoproteins. Concurrent mutation of these two key residues (E14R and A20F) in the envelope glycoprotein of the Friend murine leukemia virus (F-MLV) ISD has been reported to abolish its immunosuppressive activity, without affecting its fusogenicity, and to weaken the ability of the virus to replicate specifically in immunocompetent hosts. Here, we show that mutation of these key residues did, in fact, result in a substantial loss of F-MLV infectivity, independently of host immunity, challenging whether associations exist between the two. Notably, a loss of infectivity incurred by the F-MLV mutant with the E14R and A20F double ISD mutation was conditional on expression of the ecotropic envelope receptor murine cationic amino acid transporter-1 (mCAT1) in the virus-producing cell. Indeed, the F-MLV mutant retained infectivity when it was produced by human cells, which naturally lack mCAT1 expression, but not by murine cells. Furthermore, mCAT1 overexpression in human cells impaired the infectivity of both the F-MLV double mutant and the wild-type F-MLV strain, suggesting a finely tuned relationship between the levels of mCAT1 in the producer cell and the infectivity of the virions produced. An adverse effect on this relationship, rather than disruption of the putative ISD, is therefore more likely to explain the loss of F-MLV infectivity incurred by mutations in key ISD residues E14 and A20.
Kassiotis G, Stoye JP, 2017, Making a virtue of necessity: the pleiotropic role of human endogenous retroviruses in cancer, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 372, ISSN: 0962-8436
Like all other mammals, humans harbour an astonishing number of endogenous retroviruses (ERVs), as well as other retroelements, embedded in their genome. These remnants of ancestral germline infection with distinct exogenous retroviruses display various degrees of open reading frame integrity and replication capability. Modern day exogenous retroviruses, as well as the infectious predecessors of ERVs, are demonstrably oncogenic. Further, replication-competent ERVs continue to cause cancers in many other species of mammal. Moreover, human cancers are characterized by transcriptional activation of human endogenous retroviruses (HERVs). These observations conspire to incriminate HERVs as causative agents of human cancer. However, exhaustive investigation of cancer genomes suggests that HERVs have entirely lost the ability for re-infection and thus the potential for insertional mutagenic activity. Although there may be non-insertional mechanisms by which HERVs contribute to cancer development, recent evidence also uncovers potent anti-tumour activities exerted by HERV replication intermediates or protein products. On balance, it appears that HERVs, despite their oncogenic past, now represent potential targets for immune-mediated anti-tumour mechanisms.
Jenkins B, Eksmond U, Young G, et al., 2017, Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein, Wellcome Open Research, Vol: 1, Pages: 22-22
<ns4:p>To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs) of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II), and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of pMHC formation or TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.</ns4:p>
Jenkins B, Eksmond U, Young G, et al., 2016, Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein., Wellcome Open Research, Vol: 1, ISSN: 2398-502X
To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs) of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II), and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.
Mavrommatis B, Baudino L, Levy P, et al., 2016, Dichotomy between T Cell and B Cell Tolerance to Neonatal Retroviral Infection Permits T Cell Therapy, JOURNAL OF IMMUNOLOGY, Vol: 197, Pages: 3628-3638, ISSN: 0022-1767
Elucidation of the immune requirements for control or elimination of retroviral infection remains an important aim. We studied the induction of adaptive immunity to neonatal infection with a murine retrovirus, under conditions leading to immunological tolerance. We found that the absence of either maternal or offspring adaptive immunity permitted efficient vertical transmission of the retrovirus. Maternal immunodeficiency allowed the retrovirus to induce central Th cell tolerance in the infected offspring. In turn, this compromised the offspring’s ability to mount a protective Th cell–dependent B cell response. However, in contrast to T cells, offspring B cells were not centrally tolerized and retained their ability to respond to the infection when provided with T cell help. Thus, escape of retrovirus-specific B cells from deletional tolerance offers the opportunity to induce protective retroviral immunity by restoration of retrovirus-specific T cell help, suggesting similar T cell immunotherapies for persistent viral infections.
Donnarumma T, Young GR, Merkenschlager J, et al., 2016, Opposing Development of Cytotoxic and Follicular Helper CD4 T Cells Controlled by the TCF-1-Bcl6 Nexus, Cell Reports, Vol: 17, Pages: 1571-1583, ISSN: 2211-1247
CD4+ T cells develop distinct and often contrasting helper, regulatory, or cytotoxic activities. Typically a property of CD8+ T cells, granzyme-mediated cytotoxic T cell (CTL) potential is also exerted by CD4+ T cells. However, the conditions that induce CD4+ CTLs are not entirely understood. Using single-cell transcriptional profiling, we uncover a unique signature of Granzyme B (GzmB)+ CD4+ CTLs, which distinguishes them from other CD4+ T helper (Th) cells, including Th1 cells, and strongly contrasts with the follicular helper T (Tfh) cell signature. The balance between CD4+ CTL and Tfh differentiation heavily depends on the class of infecting virus and is jointly regulated by the Tfh-related transcription factors Bcl6 and Tcf7 (encoding TCF-1) and by the expression of the inhibitory receptors PD-1 and LAG3. This unique profile of CD4+ CTLs offers targets for their study, and its antagonism by the Tfh program separates CD4+ T cells with either helper or killer functions.
Kassiotis G, Stoye JP, 2016, Immune responses to endogenous retroelements: taking the bad with the good, NATURE REVIEWS IMMUNOLOGY, Vol: 16, Pages: 207-219, ISSN: 1474-1733
Li SX, Barrett BS, Guo K, et al., 2016, Tetherin/BST-2 promotes dendritic cell activation and function during acute retrovirus infection, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322
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- Citations: 25
Merkenschlager J, Ploquin MJ, Eksmond U, et al., 2016, Stepwise B-cell-dependent expansion of T helper clonotypes diversifies the T-cell response, Nature Communications, Vol: 7, Pages: 1-13, ISSN: 2041-1723
Antigen receptor diversity underpins adaptive immunity by providing the ground for clonal selection of lymphocytes with the appropriate antigen reactivity. Current models attribute T cell clonal selection during the immune response to T-cell receptor (TCR) affinity for either foreign or self peptides. Here, we report that clonal selection of CD4+ T cells is also extrinsically regulated by B cells. In response to viral infection, the antigen-specific TCR repertoire is progressively diversified by staggered clonotypic expansion, according to functional avidity, which correlates with self-reactivity. Clonal expansion of lower-avidity T-cell clonotypes depends on availability of MHC II-expressing B cells, in turn influenced by B-cell activation. B cells clonotypically diversify the CD4+ T-cell response also to vaccination or tumour challenge, revealing a common effect.
Merkenschlager J, Kassiotis G, 2015, Narrowing the gap: preserving repertoire diversity despite clonal selection during the CD4 T cell response, FRONTIERS IN IMMUNOLOGY, Vol: 6, Pages: 1-11, ISSN: 1664-3224
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- Citations: 6
Thorborn G, Ploquin MJ, Eksmond U, et al., 2014, Clonotypic Composition of the CD4<SUP>+</SUP> T Cell Response to a Vectored Retroviral Antigen Is Determined by Its Speed, JOURNAL OF IMMUNOLOGY, Vol: 193, Pages: 1567-1577, ISSN: 0022-1767
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- Citations: 11
Young GR, Mavrommatis B, Kassiotis G, 2014, Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes, RETROVIROLOGY, Vol: 11, ISSN: 1742-4690
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- Citations: 36
Li SX, Barrett BS, Heilman KJ, et al., 2014, Tetherin Promotes the Innate and Adaptive Cell-Mediated Immune Response against Retrovirus Infection In Vivo, JOURNAL OF IMMUNOLOGY, Vol: 193, Pages: 306-316, ISSN: 0022-1767
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- Citations: 43
Thorborn G, Young GR, Kassiotis G, 2014, Effective T helper cell responses against retroviruses: are all clonotypes equal?, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 96, Pages: 27-37, ISSN: 0741-5400
Kassiotis G, 2014, Endogenous Retroviruses and the Development of Cancer, JOURNAL OF IMMUNOLOGY, Vol: 192, Pages: 1343-1349, ISSN: 0022-1767
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- Citations: 129
Ng DHL, Skehel JJ, Kassiotis G, et al., 2014, Recovery of an Antiviral Antibody Response following Attrition Caused by Unrelated Infection, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
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- Citations: 16
Young GR, Stoye JP, Kassiotis G, 2013, Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis, BIOESSAYS, Vol: 35, Pages: 794-803, ISSN: 0265-9247
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- Citations: 58
Mavrommatis B, Young GR, Kassiotis G, 2013, Counterpoise between the microbiome, host immune activation and pathology, CURRENT OPINION IN IMMUNOLOGY, Vol: 25, Pages: 456-462, ISSN: 0952-7915
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- Citations: 12
Myers L, Joedicke JJ, Carmody AB, et al., 2013, IL-2-Independent and TNF-α-Dependent Expansion of Vβ5<SUP>+</SUP> Natural Regulatory T Cells during Retrovirus Infection, JOURNAL OF IMMUNOLOGY, Vol: 190, Pages: 5485-5495, ISSN: 0022-1767
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- Citations: 30
Young GR, Eksmond U, Salcedo R, et al., 2012, Resurrection of endogenous retroviruses in antibody-deficient mice, NATURE, Vol: 491, Pages: 774-+, ISSN: 0028-0836
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- Citations: 161
Duley AK, Ploquin MJ-Y, Eksmond U, et al., 2012, Negative Impact of IFN-γ on Early Host Immune Responses to Retroviral Infection, JOURNAL OF IMMUNOLOGY, Vol: 189, Pages: 2521-2529, ISSN: 0022-1767
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- Citations: 15
Young GR, Ploquin MJ-Y, Eksmond U, et al., 2012, Negative Selection by an Endogenous Retrovirus Promotes a Higher-Avidity CD4<SUP>+</SUP> T Cell Response to Retroviral Infection, PLOS PATHOGENS, Vol: 8, ISSN: 1553-7366
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- Citations: 40
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