Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection

Penaloza-MacMaster, Pablo; Barber, Daniel L.; Wherry, E. John; Provine, Nicholas M.; Teigler, Jeffrey E.; Parenteau, Lily; Blackmore, Stephen; Borducchi, Erica N.; Larocca, Rafael A.; Yates, Kathleen B.; Shen, Hao; Haining, W. Nicholas; Sommerstein, Rami; Pinschewer, Daniel D.; Ahmed, Rafi; Barouch, Dan H.

doi:10.1126/science.aaa2148

Cited by 69 publications

(77 citation statements)

References 42 publications

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“…LCMV is a noncytolytic virus that has been shown to cause lethality in mouse models not by direct killing of host tissues but rather by inducing a severe immunological reaction that is primarily mediated by type I interferon 30 . Normally LCMV elicits a pronounced IFNa response in mice that peaks 2–3 days after infection 29 .…”

Section: Resultsmentioning

confidence: 99%

“…IFNa can then induce a cascade of cytokines including TNFa and IL1 that promote vasodilation and circulatory collapse. 30 We thus measured the serum IFNa concentration in miR-22 KO and WT animals on day 3 following infection. Notably, WT animals mounted a strong IFNa response, while the IFNa levels in miR-22 KO were significantly lower (Figure 2C) 29 .…”

Section: Resultsmentioning

confidence: 99%

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MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

Kadmon

Landers

et al. 2017

Experimental Hematology

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MicroRNA-22 (miR-22) is a highly conserved microRNA that can regulate cell proliferation, oncogenesis, and cell maturation, especially during stress. In hematopoietic stem cells (HSCs) miR-22 has been reported to be involved in the regulation of key self-renewal factors including Tet2. Recent work demonstrates that miR-22 also participates in regulation of the interferon response, and expression profiling studies suggest that it is variably expressed at different stages in erythroid differentiation. We thus hypothesized that miR-22 regulates maturation of erythroid progenitors during stress hematopoiesis through its interaction with interferon. We compared the blood and bone marrow of wild type (WT) and miR-22-deficient mice at baseline and upon infectious challenge with systemic lymphochoriomeningitis (LCMV) virus. MiR-22-deficient mice maintained platelet counts better than WT mice during infection, but they showed significantly reduced red blood cells (RBC) and hemoglobin. Analysis of bone marrow progenitors demonstrated better overall survival and improved HSC homeostasis in infected miR-22-null mice compared to WT, attributable to a blunted interferon response to LCMV challenge in the miR-22-null mice. We found that miR-22 was exclusively expressed in stage II erythroid precursors and was downregulated upon infection in WT mice. Our results indicate that miR-22 promotes the interferon response to viral infection and that it functions at baseline as a brake to slow erythroid differentiation and maintain adequate erythroid potential. Impaired regulation of erythrogenesis in the absence of miR-22 can lead to anemia during infection.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

Kadmon

Landers

et al. 2017

Experimental Hematology

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“…Possible mechanisms of benefit include (i) reduction of Th1-driven immunopathology, (ii) support of the CD8 + T cell response, and (iii) a more canonical role for Tfh cell function, namely, providing help to enable a robust antibody response. A role for reduced immunopathology has been supported by vaccination with an LCMV CD4 + T cell epitope driving Th1 responses 68 . Mice that were immunized with the CD4 + T cell epitope experienced marked mortality after challenge with LCMV clone 13 as compared to unimmunized mice 68 .…”

Section: Cd4+ T Responses In Mouse Models Of Chronic Infectionmentioning

confidence: 99%

“…A role for reduced immunopathology has been supported by vaccination with an LCMV CD4 + T cell epitope driving Th1 responses 68 . Mice that were immunized with the CD4 + T cell epitope experienced marked mortality after challenge with LCMV clone 13 as compared to unimmunized mice 68 . This mortality was associated with an extended duration of the Th1 response, while control mice demonstrated the expected shift towards expressing transcripts associated with Tfh, Treg, and exhausted T cells 68 .…”

Section: Cd4+ T Responses In Mouse Models Of Chronic Infectionmentioning

confidence: 99%

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Vella

Herati

Wherry

2017

Trends in Molecular Medicine

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CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable Th1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host-pathogen interaction.

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“…However, excessive numbers of CD4 + T cells, caused by NK cell depletion or by vaccines that solely elicit an antiviral CD4 + T cell response, can result in pronounced inflammation and mortality during chronic LCMV infection, suggesting that enhanced CD4 + T cell responses should be sought carefully (169, 170). In the following sections we discuss key features of CD4 + T cell functional specialization and heterogeneity during chronic viral infections (Figure 2).…”

Section: Cd4+ T Cells: Distinct Functional Specialization During Chromentioning

confidence: 99%

Innate and Adaptive Immune Regulation During Chronic Viral Infections

et al. 2015

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Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8+ T cell functions, and specialization of CD4+ T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications.

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Vaccine-elicited CD4 T cells induce immunopathology after chronic LCMV infection

Cited by 69 publications

References 42 publications

MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

CD4+ T Cell Differentiation in Chronic Viral Infections: The Tfh Perspective

Innate and Adaptive Immune Regulation During Chronic Viral Infections

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