IL-10 Restricts Memory T Cell Inflation during Cytomegalovirus Infection

Jones, Matthew M.; Ladell, Kristin; Wynn, Katherine K.; Stacey, Maria A.; Quigley, Máire F.; Gostick, Emma; Price, David A.; Humphreys, Ian R.

doi:10.4049/jimmunol.1001535

Cited by 51 publications

(53 citation statements)

References 84 publications

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“…We adopted this approach to ensure adequate sampling depth and minimize bias arising from lack of coverage, which would lead to an underestimation of frequency differences between individual clonotypes. The TRBV1/TRBJ2-1 and TRBV16/TRBJ2-5 gene rearrangements selected for this study are prevalent within memory CD8 + T-cell populations specific for the M38 SSPPM-FRVP/H-2K b (unpublished data) and IE-3 RALEYKNL/H-2K b (9) epitopes derived from murine cytomegalovirus, respectively. Naïve CD8 + T cells were stringently defined by polychromatic flow cytometry according to the expression of multiple lineage and phenotypic markers (Fig.…”

Section: Resultsmentioning

confidence: 99%

Convergent recombination shapes the clonotypic landscape of the naïve T-cell repertoire

Quigley

Greenaway

Venturi

et al. 2010

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

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124

127

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Adaptive T-cell immunity relies on the recruitment of antigenspecific clonotypes, each defined by the expression of a distinct T-cell receptor (TCR), from an array of naïve T-cell precursors. Despite the enormous clonotypic diversity that resides within the naïve T-cell pool, interindividual sharing of TCR sequences has been observed within mobilized T-cell responses specific for certain peptide-major histocompatibility complex (pMHC) antigens. The mechanisms that underlie this phenomenon have not been fully elucidated, however. A mechanism of convergent recombination has been proposed to account for the occurrence of shared, or "public," TCRs in specific memory T-cell populations. According to this model, TCR sharing between individuals is directly related to TCR production frequency; this, in turn, is determined on a probabilistic basis by the relative generation efficiency of particular nucleotide and amino acid sequences during the recombination process. Here, we tested the key predictions of convergent recombination in a comprehensive evaluation of the naïve CD8 + TCRβ repertoire in mice. Within defined segments of the naïve CD8 + T-cell repertoire, TCRβ sequences with convergent features were (i) present at higher copy numbers within individual mice and (ii) shared between individual mice. Thus, the naïve CD8 + T-cell repertoire is not flat, but comprises a hierarchy of recurrence rates for individual clonotypes that is determined by relative production frequencies. These findings provide a framework for understanding the early mobilization of public CD8 + T-cell clonotypes, which can exert profound biological effects during acute infectious processes.

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Section: Resultsmentioning

confidence: 99%

Convergent recombination shapes the clonotypic landscape of the naïve T-cell repertoire

Quigley

Greenaway

Venturi

et al. 2010

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

Self Cite

124

127

View full text Add to dashboard Cite

show abstract

“…In mice, therapeutic vaccination during persistent LCMV infection, in combination with either anti-PD1 or anti-IL-10 antibodies, improves LCMV-specific T cell immunity and consequently leads to a decrease in viral load [73,74]. Blocking of IL-10 in CMV-infected mice enhances the expansion of functional memory T cells and results in reduced viral load in chronic and latent infection [53]. Based on the enhanced control of established persistent LCMV infection and restoration of virus-specific immunity when PD-1 and IL-10 are blocked [75], the combination of these antibodies might have a stronger impact on vaccineinduced immunity and clinical outcome in humans.…”

Section: Immunotherapy Of Chronic Viral Infections -A Foreseeable Futmentioning

confidence: 96%

“…Notably, EBV and CMV express genes that encode for a viral homolog of IL-10 that has the same immunosuppressive potency as human IL-10 [51]. IL-10 protein that is encoded by the CMV gene that encodes IL-10 suppresses recognition of latently infected myeloid progenitor cells by CD4 + T cells [52], and this effect can be relieved by blocking the binding of viral IL-10 to the IL-10 receptor [53]. In addition, it has been reported that chronic active EBV in EBV-infected T cells increases transcription of Il10 and Tgfb [54].…”

Section: Hbv Infectionmentioning

confidence: 99%

Immunotherapy for persistent viral infections and associated disease

Burg

Arens

Melief

2011

Trends in Immunology

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“…The cytokines IL-7 and IL-15, which are important for homeostatic proliferation of memory CD8 + T cells, have potent proliferative properties for HCMVspecific T cells in vitro [42], but their precise role for memory T cell inflation in an in vivo setting remains to be elucidated. Another important cytokine is IL-10, which clearly restricts inflation of T cells in the chronic phase of CMV infection by unknown mechanisms [43].…”

Section: Cytokinesmentioning

confidence: 99%