scholarly journals Time-resolved systems analysis reveals a critical role of XCR1+ dendritic cells in the maintenance of effector T cells during chronic viral infection

2018 ◽  
Author(s):  
Jordi Argilaguet ◽  
Mireia Pedragosa ◽  
Anna Esteve-Codina ◽  
Graciela Riera ◽  
Enric Vidal ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Chronic Infection ◽  
Critical Role ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Time Resolved ◽  
Effector T Cell

AbstractUpon a viral infection, the host immune system attempts to eradicate the virus. However, once the infection threat seems overwhelming, the infected host actively shuts down effector responses to reduce immunopathology. The price to pay for this is the establishment of a chronic infection that is only partially controlled by a lower level immune response. The genetic networks underlying this infection fate decision and the immune adaptation to the lower level response are not well understood. Here we used an integrated approach of gene coexpression network analysis of time-resolved splenic transcriptomes and immunological analysis to characterize the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections. We found first, an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.Author SummaryThe outcomes of viral infections are the result of dynamic interplays between infecting viruses and induced host responses. They can be categorized as either acute or chronic depending on temporal virus-host relationships. Chronic infections are associated with immune exhaustion, a partial shut-down of effector responses. The processes underlying infection fate decisions are incompletely understood. Here we analyzed, on a systems level, infection-fate–specific gene signatures and the resulting adaptive processes of the host. We used the well-established lymphocytic choriomeningitis virus infection mouse model which has been instrumental to detect many fundamental processes in the virus-immune system crosstalk that are also relevant in human infections. We show an early attenuation of macrophage-mediated inflammation and an involvement of cross-presenting dendritic cells in the maintenance of an antiviral cytotoxic T cell response and virus control in the chronic infection phase. Together our data demonstrate a delicate adaptation process towards a chronic virus infection with both immunosuppressive and immunostimulatory processes. We fill a knowledge gap regarding the mechanisms of effector T cell maintenance and provide a new rational for targeted therapeutic vaccination.

scholarly journals Antiviral cytotoxic T cell response induced by in vivo priming with a free synthetic peptide.

1990 ◽  
Vol 171 (5) ◽  
pp. 1815-1820 ◽  
Author(s):  
P Aichele ◽  
H Hengartner ◽  
R M Zinkernagel ◽  
M Schulz
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Lymphocytic Choriomeningitis ◽  
Effector T Cells ◽  
T Cell Response ◽  
Class I ◽  
Cytotoxic T Cell ◽  
Effector T Cell

Induction in vivo of antiviral cytotoxic T cell response was achieved in a MHC class I-dependent fashion by immunizing mice three times with a free unmodified 15-mer peptide derived from the nucleoprotein of lymphocytic choriomeningitis virus in IFA. The effector T cells are CD8+, restricted to the class I Ld allele of the analyzed mouse strain, and are specific both at the level of secondary restimulation in vitro and at the effector T cell level. These results suggest that cocktails of viral peptides may be used as antiviral T cell vaccines.

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 Loss of Resistance to Mousepox during Chronic Lymphocytic Choriomeningitis Virus Infection Is Associated with Impaired T-Cell Responses and Can Be Rescued by Immunization

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Pedro Alves-Peixoto ◽  
Maria Férez ◽  
Cory J. Knudson ◽  
Carolina R. Melo-Silva ◽  
Colby Stotesbury ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Infection ◽  
Viral Infections ◽  
Acute Infection ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Cell Responses ◽  
Chronic Viral Infections

ABSTRACT It is well established that chronic viral infections can cause immune suppression, resulting in increased susceptibility to other infectious diseases. However, the effects of chronic viral infection on T-cell responses and vaccination against highly pathogenic viruses are not well understood. We have recently shown that C57BL/6 (B6) mice lose their natural resistance to wild-type (WT) ectromelia virus (ECTV) when chronically infected with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13). Here we compared the T-cell response to ECTV in previously immunologically naive mice that were chronically infected with CL13 or that were convalescent from acute infection with the Armstrong (Arm) strain of LCMV. Our results show that mice that were chronically infected with CL13 but not those that had recovered from Arm infection have highly defective ECTV-specific CD8+ and CD4+ T-cell responses to WT ECTV. These defects are at least partly due to the chronic infection environment. In contrast to mice infected with WT ECTV, mice chronically infected with CL13 survived without signs of disease when infected with ECTV-Δ036, a mutant ECTV strain that is highly attenuated. Strikingly, mice chronically infected with CL13 mounted a strong CD8+ T-cell response to ECTV-Δ036 and survived without signs of disease after a subsequent challenge with WT ECTV. Our work suggests that enhanced susceptibility to acute viral infections in chronically infected individuals can be partly due to poor T-cell responses but that sufficient T-cell function can be recovered and resistance to acute infection can be restored by immunization with highly attenuated vaccines. IMPORTANCE Chronic viral infections may result in immunosuppression and enhanced susceptibility to infections with other pathogens. For example, we have recently shown that mice chronically infected with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13) are highly susceptible to mousepox, a disease that is caused by ectromelia virus and that is the mouse homolog of human smallpox. Here we show chronic CL13 infection severely disrupts the expansion, proliferation, activation, and cytotoxicity of T cells in response due at least in part to the suppressive effects of the chronic infection milieu. Notably, despite this profound immunodeficiency, mice chronically infected with CL13 could be protected by vaccination with a highly attenuated variant of ECTV. These results demonstrate that protective vaccination of immunosuppressed individuals is possible, provided that proper immunization tools are used.

scholarly journals CD4+ T Cells Induced by a DNA Vaccine: Immunological Consequences of Epitope-Specific Lysosomal Targeting

2001 ◽  
Vol 75 (21) ◽  
pp. 10421-10430 ◽  
Author(s):  
Fernando Rodriguez ◽  
Stephanie Harkins ◽  
Jeffrey M. Redwine ◽  
Jose M. de Pereda ◽  
J. Lindsay Whitton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Vaccine ◽  
Cell Response ◽  
T Cell Responses ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Cell Responses ◽  
Lysosomal Targeting

ABSTRACT Our previous studies have shown that targeting DNA vaccine-encoded major histocompatibility complex class I epitopes to the proteasome enhanced CD8+ T-cell induction and protection against lymphocytic choriomeningitis virus (LCMV) challenge. Here, we expand these studies to evaluate CD4+ T-cell responses induced by DNA immunization and describe a system for targeting proteins and minigenes to lysosomes. Full-length proteins can be targeted to the lysosomal compartment by covalent attachment to the 20-amino-acid C-terminal tail of lysosomal integral membrane protein-II (LIMP-II). Using minigenes encoding defined T-helper epitopes from lymphocytic choriomeningitis virus, we show that the CD4+T-cell response induced by the NP309–328 epitope of LCMV was greatly enhanced by addition of the LIMP-II tail. However, the immunological consequence of lysosomal targeting is not invariably positive; the CD4+ T-cell response induced by the GP61–80 epitope was almost abolished when attached to the LIMP-II tail. We identify the mechanism which underlies this marked difference in outcome. The GP61–80 epitope is highly susceptible to cleavage by cathepsin D, an aspartic endopeptidase found almost exclusively in lysosomes. We show, using mass spectrometry, that the GP61–80 peptide is cleaved between residues F74 and K75 and that this destroys its ability to stimulate virus-specific CD4+ T cells. Thus, the immunological result of lysosomal targeting varies, depending upon the primary sequence of the encoded antigen. We analyze the effects of CD4+ T-cell priming on the virus-specific antibody and CD8+ T-cell responses which are mounted after virus infection and show that neither response appears to be accelerated or enhanced. Finally, we evaluate the protective benefits of CD4+ T-cell vaccination in the LCMV model system; in contrast to DNA vaccine-induced CD8+ T cells, which can confer solid protection against LCMV challenge, DNA vaccine-mediated priming of CD4+ T cells does not appear to enhance the vaccinee's ability to combat viral challenge.

scholarly journals Recruitment Times, Proliferation, and Apoptosis Rates during the CD8+ T-Cell Response to Lymphocytic Choriomeningitis Virus

2001 ◽  
Vol 75 (22) ◽  
pp. 10663-10669 ◽  
Author(s):  
Rob J. De Boer ◽  
Mihaela Oprea ◽  
Rustom Antia ◽  
Kaja Murali-Krishna ◽  
Rafi Ahmed ◽  
...  
Keyword(s):  
T Cell ◽  
Population Size ◽  
Cell Response ◽  
Average Rate ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
T Cell Response ◽  
Cell Stimulation ◽  
T Cell Stimulation ◽  
Death Phase

ABSTRACT The specific CD8+ T-cell response during acute lymphocytic choriomeningitis virus (LCMV) infection of mice is characterized by a rapid proliferation phase, followed by a rapid death phase and long-term memory. In BALB/c mice the immunodominant and subdominant CD8+ responses are directed against the NP118 and GP283 epitopes. These responses differ mainly in the magnitude of the epitope-specific CD8+ T-cell expansion. Using mathematical models together with a nonlinear parameter estimation procedure, we estimate the parameters describing the rates of change during the three phases and thereby establish the differences between the responses to the two epitopes. We find that CD8+ cell proliferation begins 1 to 2 days after infection and occurs at an average rate of 3 day−1, reaching the maximum population size between days 5 and 6 after immunization. The 10-fold difference in expansion to the NP118 and GP283 epitopes can be accounted for in our model by a 3.5-fold difference in the antigen concentration of these epitopes at which T-cell stimulation is half-maximal. As a consequence of this 3.5-fold difference in the epitope concentration needed for T-cell stimulation, the rates of activation and proliferation of T cells specific for the two epitopes differ during the response and in combination can account for the large difference in the magnitude of the response. After the peak, during the death phase, the population declines at a rate of 0.5 day−1, i.e., cells have an average life time of 2 days. The model accounts for a memory cell population of 5% of the peak population size by a reversal to memory of 1 to 2% of the activated cells per day during the death phase.

T-cell intrinsic expression of MyD88 is required for sustained expansion of the virus-specific CD8+ T-cell population in LCMV-infected mice

2009 ◽  
Vol 90 (2) ◽  
pp. 423-431 ◽  
Author(s):  
Christina Bartholdy ◽  
Jeanette E. Christensen ◽  
Mirjana Grujic ◽  
Jan P. Christensen ◽  
Allan R. Thomsen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cell Response ◽  
Acute Infection ◽  
Critical Role ◽  
Systemic Infection ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Response ◽  
Cell Expression

Acute infection with lymphocytic choriomeningitis virus (LCMV) normally results in robust clonal expansion of virus-specific CD8+ T cells, which in turn control the primary infection. However, similar infection of myeloid differentiation factor 88 (MyD88)-deficient mice leads to a markedly impaired T-cell response and chronic infection. It has been found previously that impairment of the innate immune response is not sufficient to explain this profound change in outcome. Using adoptive transfer of CD8+ T cells, this study demonstrated unequivocally that T-cell expression of MyD88 is critical for a normal T-cell response to LCMV. In addition, it was found that expression of MyD88 is superfluous during early activation and proliferation of the antigen-activated CD8+ T cells, but plays a critical role in the sustained expansion of the antigen-specific CD8+ T-cell population during the primary T-cell response. Interestingly, a critical role for MyD88 was evident only under conditions of systemic infection with virus capable of causing prolonged infection, suggesting that MyD88 expression may function as an internal regulator of the threshold for antigen-driven, exhaustive differentiation.

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