Cell-Intrinsic Defects in the Proliferative Response of Antiviral Memory CD8 T Cells in Aged Mice upon Secondary Infection

Decman, Vilma; Laidlaw, Brian J.; DiMenna, Lauren J.; Abdulla, Sarah; Mozdzanowska, Krystyna; Erikson, Jan; Ertl, Hildegund C. J.; Wherry, E. John

doi:10.4049/jimmunol.0902063

Cited by 64 publications

(76 citation statements)

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“…Recombinant influenza virus containing the LCMV GP33-41 epitope inserted into the neuraminidase protein stalk region was provided by R. Webby (St. Jude Children’s Research Hospital, Memphis, TN) 51–53 . These recombinant influenza virus strains replicate and exhibit pathogenicity similar to that of their non-recombinant counterparts 52 . Viral titers in lungs were determined by qPCR as described 51 .…”

Section: Methodsmentioning

confidence: 99%

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

et al. 2017

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During infection, antigen-specific T cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. We found that the microRNA miR-31 was strongly induced by activation of the T cell antigen receptor (TCR) in a pathway involving calcium and activation of the transcription factor NFAT. During chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13, miR-31-deficent mice recovered from clinical disease, while wild-type mice continued to show signs of disease. This disease phenotype was explained by the presence of larger numbers of cytokine-secreting LCMV-specific CD8+ T cells in miR-31-deficent mice than in wild-type mice. Mechanistically, miR-31 increased the sensitivity of T cells to type I interferons, which interfered with effector T cell function and increased the expression of several proteins related to T cell dysfunction during chronic infection. These studies identify miR-31 as an important regulator of T cell exhaustion in chronic infection.

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Section: Methodsmentioning

confidence: 99%

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

et al. 2017

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“…Furthermore, peak GZMA mRNA expression was reduced in aged ferrets (Figure 3 ix). Together, these findings suggest a potential age-related decrease in type 1 T-cell responses specific to heterologous 2° challenge which may have contributed to disease (Bender and Small, 1993; Decman et al, 2010). …”

Section: Resultsmentioning

confidence: 87%

“…Heterosubtypic influenza A immune memory is severely impaired in aged animals (Bender and Small, 1993; Decman et al, 2010), although the elderly's sensitivity to monosubtypic antigenic change is unclear. To address this question, we investigated clinical morbidity, viral dynamics, and subsequent immune responses to sequential influenza A H1N1 infection for the first time in an aged ferret model.…”

Section: Introductionmentioning

confidence: 99%

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

et al. 2014

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The major burden of influenza morbidity resides within the elderly population. The challenge managing influenza-associated illness in the elderly is the decline of immune function, where mechanisms leading to immunological senescence have not been elucidated. To better represent the immune environment, we investigated clinical morbidity and immune function during sequential homologous and heterologous H1N1 influenza infection in an aged ferret model. Our findings demonstrated experimentally that aged ferrets had significant morbidity during monosubtypic heterologous 2° challenge with significant weight loss and respiratory symptoms. Furthermore, increased clinical morbidity was associated with slower and shorter hemagglutinin antibody generation and attenuated type 1 T-cell gene responses in peripheral blood. These results revealed dampened immune activation during sequential influenza infection in aged ferrets. With the presence of an aged model, dissecting clinical morbidity, viral dynamics and immune response during influenza infection will aid the development of future prophylactics such as age specific influenza vaccines.

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“…Normal aging is associated with increased health risk, as vaccine efficacy wanes and susceptibility to, and severity of, a variety of infections and malignancies is enhanced (1,2). Whereas aging compromises a number of arms of the immune system (3), studies in mice and humans have demonstrated deficits that are intrinsic to naïve CTL populations (4)(5)(6). Thus, a complete understanding of both age-related CTL deficiencies and the underlying mechanisms is critical.…”

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confidence: 99%

Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8 ⁺ T cells in aged mice

Quinn

Zaloumis

Cukalac

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In advanced age, decreased CD8 + cytotoxic T-lymphocyte (CTL) responses to novel pathogens and cancer is paralleled by a decline in the number and function of naïve CTL precursors (CTLp). Although the age-related fall in CD8 + T-cell numbers is well established, neither the underlying mechanisms nor the extent of variation for different epitope specificities have been defined. Furthermore, naïve CD8 + T cells expressing high levels of CD44 accumulate with age, but it is unknown whether this accumulation reflects their preferential survival or an age-dependent driver of CD8 + T-cell proliferation. Here, we track the number and phenotype of four influenza A virus (IAV)-specific CTLp populations in naïve C57BL/6 (B6) mice during aging, and compare T-cell receptor (TCR) clonal diversity for the CD44hi and CD44lo subsets of one such population. We show differential onset of decline for several IAV-specific CD8 + T-cell populations with advanced age that parallel age-associated changes in the B6 immunodominance hierarchy, suggestive of distinct impacts of aging on different epitope-specific populations. Despite finding no evidence of clonal expansions in an aged, epitope-specific TCR repertoire, nonrandom alterations in TCR usage were observed, along with elevated CD5 and CD8 coreceptor expression. Collectively, these data demonstrate that naïve CD8 + T cells expressing markers of heightened selfrecognition are selectively retained, but not clonally expanded, during aging.critical for the control of viruses and tumors, specific defects are likely to contribute substantially to overall immune dysfunction. Normal aging is associated with increased health risk, as vaccine efficacy wanes and susceptibility to, and severity of, a variety of infections and malignancies is enhanced (1, 2). Whereas aging compromises a number of arms of the immune system (3), studies in mice and humans have demonstrated deficits that are intrinsic to naïve CTL populations (4-6). Thus, a complete understanding of both age-related CTL deficiencies and the underlying mechanisms is critical.The magnitude of the response, the diversity of T-cell receptor (TCR)-defined clonal recruitment, and the avidity of TCR binding to cognate peptides in complex with MHC class I glycoproteins (pMHCI) are all key determinants of CTL response efficacy (7). Each of these factors is substantially constrained by their respective characteristics in the naive CTL precursor (CTLp) pool (7-10). During aging, both the number and TCR diversity of naïve polyclonal and epitope-specific CD8 + T-cell sets decreases (11-13). In addition, a large proportion (∼60-80%) of the remaining naïve CD8 + T cells, termed virtual memory (T VM ) cells, express high levels of CD44, traditionally regarded as a marker of T-cell activation and suggestive of proliferation (14). It is unclear whether the accumulation of T VM cells with age (15) represents preferential retention, de novo generation, or expansion of the T VM subset. TCR repertoire analyses show emerging TCR bias with age (11,13,16)...

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Cell-Intrinsic Defects in the Proliferative Response of Antiviral Memory CD8 T Cells in Aged Mice upon Secondary Infection

Cited by 64 publications

References 50 publications

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8 ⁺ T cells in aged mice

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Cell-Intrinsic Defects in the Proliferative Response of Antiviral Memory CD8 T Cells in Aged Mice upon Secondary Infection

Cited by 64 publications

References 50 publications

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8 + T cells in aged mice

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Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8 ⁺ T cells in aged mice