scholarly journals Immune response against lymphocytic choriomeningitis virus infection in mice without CD8 expression.

1991 ◽  
Vol 174 (6) ◽  
pp. 1425-1429 ◽  
Author(s):  
W P Fung-Leung ◽  
T M Kündig ◽  
R M Zinkernagel ◽  
T W Mak
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Mutant Mice ◽  
Cd4 T Cell ◽  
Wild Type ◽  
Lcmv Infection

The immune response against lymphocytic choriomeningitis virus (LCMV) was studied in a mutant mouse strain that does not possess CD8+ T lymphocytes. Virus-specific cytotoxic T cell activity was generated in spleens of wild-type mice in an acute LCMV infection but was not measurable in mutant mice. Injection of replicating LCMV into footpads of wild-type mice induced a CD8+ T cell-mediated swelling that peaked on day 8, followed by a CD4+ T cell-mediated swelling that peaked on day 11, whereas mutant mice exhibited only the CD4+ T cell-mediated swelling. After intracerebral inoculation with LCMV-Armstrong, all wild-type mice died of classical CD8+ T cell-dependent choriomeningitis in 8-10 days. Mutant mice showed symptoms of general malaise but most of them survived. Mutant mice depleted of CD4+ T cells by monoclonal antibody treatment showed no clinical signs of sickness. On day 9 after intravenous infection with LCMV-WE, virus was detected at high titers in spleens and livers of mutant mice but not in those of wild-type mice. On day 70 after injection of LCMV-WE into footpads, virus was not detected in wild-type mice and in one of the three mutant mice tested, but was still measurable in kidneys of the other two mutant mice. These results confirm in a new animal model that CD8+ T cell-mediated immunity is crucial in LCMV clearance and in the immunopathological disease during LCMV infection. In addition, our results demonstrated a less severe form of choriomeningitis mediated by CD4+ T cells and slow clearance of LCMV by alternative pathways independent of CD8+ T cells.

Platelets Mediate Clearance of Lymphocytic Choriomeningitis Virus Infection Preventing Lethal Hemorrhage.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1089-1089
Author(s):  
Matteo Iannacone ◽  
Giovanni Sitia ◽  
Masanori Isogawa ◽  
Jason K. Whitmire ◽  
Patrizia Marchese ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Viral Clearance ◽  
Hemorrhagic Diathesis ◽  
Platelet Dysfunction ◽  
Lcmv Infection

Abstract Lymphocytic choriomeningitis virus (LCMV) is a noncytopathic mouse pathogen of the arenaviridae family. Acute LCMV infection in adult mice has been extensively studied and found to be systemic, essentially asymptomatic and associated with a bone marrow aplasia that produces a transient pancytopenic state. The initial lymphopenia is rapidly reversed, such that within one week of LCMV exposure the mice display lymphocytosis and clear the infection through a response mediated by virus-specific cytotoxic T cells (CTLs). In spite of the thrombocytopenia, the occurrence of hemorrhage in these animals has not been previously investigated, likely because of the lack of overt bleeding symptoms. Other arenaviruses (such as Lassa and Junin) produce systemic infections in humans and cause hemorrhagic diseases that are often lethal. Hemorrhage, mostly mucosal and cutaneous, occurs in the context of profound thrombocytopenia (characteristic of Junin infection) and/or platelet dysfunction (characteristic of Lassa infection), but without disseminated intravascular coagulation (DIC) or other coagulation defects. The pathogenesis of arenavirus infections in humans remains elusive, although disease severity has been associated with the extent of hemorrhage, impaired cellular immunity and lack of viral clearance. We recently showed that platelets may contribute to viral pathogenesis by facilitating the accumulation of virus-specific CTLs at sites of infection. Thus, we reasoned that the thrombocytopenia and/or platelet dysfunction that typify arenavirus infections in humans might not only predispose to the development of hemorrhage but also compromise CTL-mediated viral clearance. Here we report our studies based on the model of LCMV infection in mice. We found that normal inbred mice infected with different isolates of LCMV develop thrombocytopenia associated with decreased platelet function, but show only limited mucosal hemorrhage prior to CD8+ T cell-mediated viral clearance. In contrast, mice depleted of platelets, but not those given anticoagulant treatment, fail to produce a normal CD8+ T cell response or clear LCMV; instead, they develop an interferon (IFN)-α/β-dependent lethal hemorrhagic infection. Transfusion of normal but not activation-blocked platelets into these animals restored the CD8+ T cell responses and allowed clearance of the infection, preventing hemorrhage and death. These results indicate that activated platelets are required for CD8+ T cells to clear LCMV infection and for protecting the host against the induction of an IFN-α/β-dependent, lethal hemorrhagic diathesis.

Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 4928-4938 ◽  
Author(s):  
Patricia Ribeiro-dos-Santos ◽  
Emma L. Turnbull ◽  
Marta Monteiro ◽  
Agnès Legrand ◽  
Karen Conrod ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Cell Functions ◽  
Chronic Hiv Infection

Abstract CD8 T cells lose the capacity to control HIV infection, but the extent of the impairment of CD8 T-cell functions and the mechanisms that underlie it remain controversial. Here we report an extensive ex vivo analysis of HIV-specific CD8 T cells, covering the expression of 16 different molecules involved in CD8 function or differentiation. This approach gave remarkably homogeneous readouts in different donors and showed that CD8 dysfunction in chronic HIV infection was much more severe than described previously: some Ifng transcription was observed, but most cells lost the expression of all cytolytic molecules and Eomesodermin and T-bet by chronic infection. These results reveal a cellular mechanism explaining the dysfunction of CD8 T cells during chronic HIV infection, as CD8 T cells are known to maintain some functionality when either of these transcription factors is present, but to lose all cytotoxic activity when both are not expressed. Surprisingly, they also show that chronic HIV and lymphocytic choriomeningitis virus infections have a very different impact on fundamental T-cell functions, “exhausted” lymphocytic choriomeningitis virus-specific cells losing the capacity to secrete IFN-γ but maintaining some cytotoxic activity as granzyme B and FasL are overexpressed and, while down-regulating T-bet, up-regulating Eomesodermin expression.

scholarly journals The CD8+ T-Cell Response to Lymphocytic Choriomeningitis Virus Involves the L Antigen: Uncovering New Tricks for an Old Virus

2007 ◽  
Vol 81 (10) ◽  
pp. 4928-4940 ◽  
Author(s):  
Maya F. Kotturi ◽  
Bjoern Peters ◽  
Fernando Buendia-Laysa ◽  
John Sidney ◽  
Carla Oseroff ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Response ◽  
Cellular Response ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Ifn Γ ◽  
Lcmv Infection

ABSTRACT CD8+ T-cell responses control lymphocytic choriomeningitis virus (LCMV) infection in H-2b mice. Although antigen-specific responses against LCMV infection are well studied, we found that a significant fraction of the CD8+ CD44hi T-cell response to LCMV in H-2b mice was not accounted for by known epitopes. We screened peptides predicted to bind major histocompatibility complex class I and overlapping 15-mer peptides spanning the complete LCMV proteome for gamma interferon (IFN-γ) induction from CD8+ T cells derived from LCMV-infected H-2b mice. We identified 19 novel epitopes. Together with the 9 previously known, these epitopes account for the total CD8+ CD44hi response. Thus, bystander T-cell activation does not contribute appreciably to the CD8+ CD44hi pool. Strikingly, 15 of the 19 new epitopes were derived from the viral L polymerase, which, until now, was not recognized as a target of the cellular response induced by LCMV infection. The L epitopes induced significant levels of in vivo cytotoxicity and conferred protection against LCMV challenge. Interestingly, protection from viral challenge was best correlated with the cytolytic potential of CD8+ T cells, whereas IFN-γ production and peptide avidity appear to play a lesser role. Taken together, these findings illustrate that the LCMV-specific CD8+ T-cell response is more complex than previously appreciated.

scholarly journals Quantitating the Magnitude of the Lymphocytic Choriomeningitis Virus-Specific CD8 T-Cell Response: It Is Even Bigger than We Thought

2006 ◽  
Vol 81 (4) ◽  
pp. 2002-2011 ◽  
Author(s):  
David Masopust ◽  
Kaja Murali-Krishna ◽  
Rafi Ahmed
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cell Expansion ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Cell Responses

ABSTRACT Measuring the magnitudes and specificities of antiviral CD8 T-cell responses is critical for understanding the dynamics and regulation of adaptive immunity. Despite many excellent studies, the accurate measurement of the total CD8 T-cell response directed against a particular infection has been hampered by an incomplete knowledge of all CD8 T-cell epitopes and also by potential contributions of bystander expansion among CD8 T cells of irrelevant specificities. Here, we use several techniques to provide a more complete accounting of the CD8 T-cell response generated upon infection of C57BL/6 mice with lymphocytic choriomeningitis virus (LCMV). Eight days following infection, we found that 85 to 95% of CD8 T cells exhibit an effector phenotype as indicated by granzyme B, 1B11, CD62L, CD11a, and CD127 expression. We demonstrate that CD8 T-cell expansion is due to cells that divide >7 times, whereas heterologous viral infections only elicited <3 divisions among bystander memory CD8 T cells. Furthermore, we found that approximately 80% of CD8 T cells in spleen were specific for ten different LCMV-derived epitopes at the peak of primary infection. These data suggest that following a single LCMV infection, effector CD8 T cells divide ≥15 times and account for at least 80%, and possibly as much as 95%, of the CD8 T-cell pool. Moreover, the response targeted a very broad array of peptide major histocompatibility complexes (MHCs), even though we examined epitopes derived from only two of the four proteins encoded by the LCMV genome and C57BL/6 mice only have two MHC class I alleles. These data illustrate the potential enormity, specificity, and breadth of CD8 T-cell responses to viral infection and demonstrate that bystander activation does not contribute to CD8 T-cell expansion.

scholarly journals Comprehensive Analysis of Cell Population Dynamics and Related Core Genes During Vitiligo Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Jingzhan Zhang ◽  
Shirong Yu ◽  
Wen Hu ◽  
Man Wang ◽  
Dilinuer Abudoureyimu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Healthy Controls ◽  
Cell Abundance

Vitiligo is a common immune-related depigmentation condition, and its pathogenesis remains unclear. This study used a combination of bioinformatics methods and expression analysis techniques to explore the relationship between immune cell infiltration and gene expression in vitiligo. Previously reported gene expression microarray data from the skin (GSE53146 and GSE75819) and peripheral blood (GSE80009 and GSE90880) of vitiligo patients and healthy controls was used in the analysis. R software was used to filter the differentially expressed genes (DEGs) in each dataset, and the KOBAS 2.0 server was used to perform functional enrichment analysis. Compared with healthy controls, the upregulated genes in skin lesions and peripheral blood leukocytes of vitiligo patents were highly enriched in immune response pathways and inflammatory response signaling pathways. Immunedeconv software and the EPIC method were used to analyze the expression levels of marker genes to obtain the immune cell population in the samples. In the lesional skin of vitiligo patients, the proportions of macrophages, B cells and NK cells were increased compared with healthy controls. In the peripheral blood of vitiligo patients, CD8+ T cells and macrophages were significantly increased. A coexpression analysis of the cell populations and DEGs showed that differentially expressed immune and inflammation response genes had a strong positive correlation with macrophages. The TLR4 receptor pathway, interferon gamma-mediated signaling pathway and lipopolysaccharide-related pathway were positively correlated with CD4+ T cells. Regarding immune response-related genes, the overexpression of IFITM2, TNFSF10, GZMA, ADAMDEC1, NCF2, ADAR, SIGLEC16, and WIPF2 were related to macrophage abundance, while the overexpression of ICOS, GPR183, RGS1, ILF2 and CD28 were related to CD4+ T cell abundance. GZMA and CXCL10 expression were associated with CD8+ T cell abundance. Regarding inflammatory response-related genes, the overexpression of CEBPB, ADAM8, CXCR3, and TNIP3 promoted macrophage infiltration. Only ADORA1 expression was associated with CD4+ T cell infiltration. ADAM8 and CXCL10 expression were associated with CD8+ T cell abundance. The overexpression of CCL18, CXCL10, FOS, NLRC4, LY96, HCK, MYD88, and KLRG1, which are related to inflammation and immune responses, were associated with macrophage abundance. We also found that immune cells infiltration in vitiligo was associated with antigen presentation-related genes expression. The genes and pathways identified in this study may point to new directions for vitiligo treatment.

scholarly journals PD-L1 Checkpoint Inhibition Narrows the Antigen-Specific T Cell Receptor Repertoire in Chronic Lymphocytic Choriomeningitis Virus Infection

2020 ◽  
Vol 94 (18) ◽  
Author(s):  
S. Klein ◽  
D. Ghersi ◽  
M. P. Manns ◽  
I. Prinz ◽  
M. Cornberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Tcr Repertoire ◽  
Lcmv Infection

ABSTRACT Checkpoint inhibitors are effective in restoring exhausted CD8+ T cell responses in persistent viral infections or tumors. Several compounds are in clinical use for different malignancies, but trials in patients with chronic viral infections have also been conducted. In a mouse model of persistent lymphocytic choriomeningitis virus (LCMV) infection, it was shown that checkpoint inhibitor treatment increased T cell proliferation and functionality, but its influence on the antigen-specific T cell receptor (TCR) repertoire is unknown. NP396-specific CD8+ T cells dominate during acute LCMV infection and are predominantly exhausted during chronic infection. Next-generation sequencing of NP396-specific TCRs showed that exhaustion corresponds with a significantly reduced NP396-specific TCR repertoire diversity: Shannon indices of 4 in immunized mice to 2.6 in persistently infected mice. Anti-PD-L1 treatment during persistent LCMV infection restored NP396-specific T cell responses and reduced viral titers. Nevertheless, anti-PD-L1-treated mice showed an even more narrowed TCR repertoire, with reduced TCR diversity compared to that of persistently infected control mice (Shannon indices of 2.1 and 2.6, respectively). Interestingly, anti-PD-L1 treatment-induced narrowing of the TCR repertoire negatively correlates with functional and physical restoration of the antigen-specific T cell response. Further, we found that private, hyperexpanded TCR clonotypes dominated the T cell response after anti-PD-L1 treatment. Although being private, these top clonotypes from anti-PD-L1-treated mice revealed a more closely related CDR3 motif than those of top clonotypes from persistently infected control mice. In conclusion, although targeting the PD-1/PD-L1 pathway reinvigorates exhausted CD8+ T cells, it fails to restore T cell repertoire diversity. IMPORTANCE Checkpoint inhibitors are effective immunotherapeutics to restore cancer- and virus-induced exhausted CD8+ T cells, by enhancing the quality and survival of immune responses. Although checkpoint inhibitors are already used as therapy against various cancers, not much is known about their multifaceted impact on the exhausted CD8+ T cell receptor (TCR) repertoire. This report describes for the first time the evolvement of an exhausted antigen-specific CD8+ TCR repertoire under checkpoint inhibitor treatment. By using a well-established virus model, we were able to show major shifts toward oligoclonality of the CD8+ TCR repertoire response against a massively exhausted lymphocytic choriomeningitis virus (LCMV) epitope. While supporting viral control in the LCMV model, oligoclonality and more private of TCR repertoires may impact future pathogenic challenges and may promote viral escape. Our results may explain the ongoing problems of viral escapes, unpredictable autoimmunity, and heterogeneous responses appearing as adverse effects of checkpoint inhibitor treatments.

scholarly journals Aplastic Anemia Rescued by Exhaustion of Cytokine-secreting CD8+ T Cells in Persistent Infection with Lymphocytic Choriomeningitis Virus

1998 ◽  
Vol 187 (11) ◽  
pp. 1903-1920 ◽  
Author(s):  
Daniel Binder ◽  
Maries F. van den Broek ◽  
David Kägi ◽  
Horst Bluethmann ◽  
Jörg Fehr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aplastic Anemia ◽  
Cd8 T Cells ◽  
Residual Disease ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Ifn Γ ◽  
Lcmv Infection

Aplastic anemia may be associated with persistent viral infections that result from failure of the immune system to control virus. To evaluate the effects on hematopoiesis exerted by sustained viral replication in the presence of activated T cells, blood values and bone marrow (BM) function were analyzed in chronic infection with lymphocytic choriomeningitis virus (LCMV) in perforin-deficient (P0/0) mice. These mice exhibit a vigorous T cell response, but are unable to eliminate the virus. Within 14 d after infection, a progressive pancytopenia developed that eventually was lethal due to agranulocytosis and thrombocytopenia correlating with an increasing loss of morphologically differentiated, pluripotent, and committed progenitors in the BM. This hematopoietic disease caused by a noncytopathic chronic virus infection was prevented by depletion of CD8+, but not of CD4+, T cells and accelerated by increasing the frequency of LCMV-specific CD8+ T cells in T cell receptor (TCR) transgenic (tg) mice. LCMV and CD8+ T cells were found only transiently in the BM of infected wild-type mice. In contrast, increased numbers of CD8+ T cells and LCMV persisted at high levels in antigen-presenting cells of infected P0/0 and P0/0 × TCR tg mice. No cognate interaction between the TCR and hematopoietic progenitors presenting either LCMV-derived or self-antigens on the major histocompatibility complex was found, but damage to hematopoiesis was due to excessive secretion and action of tumor necrosis factor (TNF)/lymphotoxin (LT)-α and interferon (IFN)-γ produced by CD8+ T cells. This was studied in double-knockout mice that were genetically deficient in perforin and TNF receptor type 1. Compared with P0/0 mice, these mice had identical T cell compartments and T cell responses to LCMV, yet they survived LCMV infection and became life-long virus carriers. The numbers of hematopoietic precursors in the BM were increased compared with P0/0 mice after LCMV infection, although transient blood disease was still noticed. This residual disease activity was found to depend on IFN-γ–producing LCMV-specific T cells and the time point of hematopoietic recovery paralleled disappearance of these virus-specific, IFN-γ–producing CD8+ T cells. Thus, in the absence of IFN-γ and/or TNF/LT-α, exhaustion of virus-specific T cells was not hampered.

scholarly journals Chronic LCMV Infection Is Fortified with Versatile Tactics to Suppress Host T Cell Immunity and Establish Viral Persistence

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1951
Author(s):  
Caleb J. Studstill ◽  
Bumsuk Hahm
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Persistence ◽  
Lymphocytic Choriomeningitis ◽  
Cd4 T Cell ◽  
Mechanistic Study ◽  
T Cell Suppression ◽  
Cell Immunity ◽  
Cell Suppression ◽  
Lcmv Infection

Ever since the immune regulatory strains of lymphocytic choriomeningitis virus (LCMV), such as Clone 13, were isolated, LCMV infection of mice has served as a valuable model for the mechanistic study of viral immune suppression and virus persistence. The exhaustion of virus-specific T cells was demonstrated during LCMV infection, and the underlying mechanisms have been extensively investigated using LCMV infection in mouse models. In particular, the mechanism for gradual CD8+ T cell exhaustion at molecular and transcriptional levels has been investigated. These studies revealed crucial roles for inhibitory receptors, surface markers, regulatory cytokines, and transcription factors, including PD-1, PSGL-1, CXCR5, and TOX in the regulation of T cells. However, the action mode for CD4+ T cell suppression is largely unknown. Recently, sphingosine kinase 2 was proven to specifically repress CD4+ T cell proliferation and lead to LCMV persistence. As CD4+ T cell regulation was also known to be important for viral persistence, research to uncover the mechanism for CD4+ T cell repression could help us better understand how viruses launch and prolong their persistence. This review summarizes discoveries derived from the study of LCMV in regard to the mechanisms for T cell suppression and approaches for the termination of viral persistence with special emphasis on CD8+ T cells.

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