TLR-Activated Dendritic Cells Enhance the Response of Aged Naive CD4 T Cells via an IL-6–Dependent Mechanism

Jones, Stephen C.; Brahmakshatriya, Vinayak; Huston, Gail E.; Dibble, John; Swain, Susan L.

doi:10.4049/jimmunol.0901296

Cited by 46 publications

(68 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, ␥␦ T cell compromise also contributed to reduced effector T cell responses, as these cells promote DC maturation via cross talk during WNV infection (50). TLR-activated DCs enhanced CD4 ϩ T cell responses in old mice via cytokinedependent mechanisms (51). Our results showed that R848 induced a robust inflammatory cytokine response and higher MHC II expression in old DCs, which in turn triggered more T cell proliferation during in vitro coculture.…”

Section: Discussionmentioning

confidence: 50%

Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice

Xie

Luo

Pang

et al. 2016

J Virol

View full text Add to dashboard Cite

The elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), a mosquito-borne flavivirus, has induced severe neurological symptoms, mostly in the elderly population. No vaccines are available for human use. Recent work showed that an attenuated WNV, a nonstructural (NS) 4B-P38G mutant, induced no lethality but strong immune responses in young (6-to 10-week-old) mice. While studying protective efficacy, we found unexpectedly that old (21-to 22-month) mice were susceptible to WNV NS4B-P38G mutant infection but were protected from subsequent lethal wild-type WNV challenge. Compared to responses in young mice, the NS4B-P38G mutant triggered higher inflammatory cytokine and interleukin-10 (IL-10) production, a delayed ␥␦ T cell expansion, and lower antibody and WNVspecific T cell responses in old mice. Toll-like receptor 7 (TLR7) is expressed on multiple types of cells. Impaired TLR7 signaling in old mice led to dendritic cell (DC) antigen-presenting function compromise and a reduced ␥␦ T cell and regulatory T cell (Treg) expansion during NS4B-P38G mutant infection. R848, a TLR7 agonist, decreased host vulnerability in NS4B-P38G-infected old mice by enhancing ␥␦ T cell and Treg expansion and the antigen-presenting capacity of DCs, thereby promoting T cell responses. In summary, our results suggest that dysregulation of TLR7 partially contributes to impaired innate and adaptive T cell responses and an enhanced vulnerability in old mice during WNV NS4B-P38G mutant infection. R848 increases the safety and efficacy during immunization of old mice with the WNV NS4B-P38G mutant. IMPORTANCEThe elderly are known to have enhanced susceptibility to infections and an impaired capacity to respond to vaccination. West Nile virus (WNV), an emerging mosquito-borne flavivirus, has induced severe neurological symptoms more frequently in the elderly population. No vaccines are available for human use. Here, we used an aged mouse model to investigate the protective efficacy of an attenuated WNV, the nonstructural 4B-P38G mutant, which was previously shown to induce no lethality but strong immune responses in young adult mice. Studies that contribute to a mechanistic understanding of immune defects in the elderly will allow the development of strategies to improve responses to infectious diseases and to increase vaccine efficacy and safety in aging individuals.

show abstract

Section: Discussionmentioning

confidence: 50%

Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice

Xie

Luo

Pang

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…We have also found in murine studies that IL-6 plays a key role in enhancing expansion and survival of older adult naive CD4 + T-cells [10, 14]. Based on our observation of a major decline in the production of IL-2 in aged human PBMC in response to influenza challenge (unpublished data) and in vitro studies in the mouse, we designed experiments to evaluate the effect of possible key cytokines including IL-2, IL-6, IL-4, IL-10, and IL-17A, on the generation of cytotoxic effector CD8 + T cells in response to influenza virus.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, TLR-stimulation of dendritic cells (DC) can induce high IL-6 levels during cognate interaction, causing the responding T cells to produce more IL-2 [14]. In this current study, we examined the effects of IL-2 and IL-6 on the CD8 + T cell response to influenza virus and showed that the addition of these cytokines restored the response to influenza in aged mice to that observed in young mice.…”

Section: Introductionmentioning

confidence: 93%

IL-2 and IL-6 cooperate to enhance the generation of influenza-specific CD8 T cells responding to live influenza virus in aged mice and humans

et al. 2016

Self Cite

View full text Add to dashboard Cite

An age-related decline in cytolytic activity has been described in CD8+ T cells and we have previously shown that the poor CD8+ effector T cell responses to influenza A/H3N2 challenge result from a decline in the proportion and function of these cytolytic T lymphocytes (CTL). Here, we describe that addition of exogenous cytokines to influenza-stimulated PBMC from both aged mice and humans, enhances the generation of influenza specific CD8 CTL by increasing their proliferation and survival. Our data show that the addition of IL-2 and IL-6 to splenocytes from mice previously infected with influenza virus restores the aged CD8+ T cell response to that observed in young mice. In humans, IL-2 plus IL-6 also reduces the proportion of apoptotic effector CD8+ T cells to levels resembling those of younger adults. In HLA-A2+ donors, MHC Class I tetramer staining showed that adding both exogenous IL-2 and IL-6 resulted in greater differentiation into influenza-specific effector CD8+ T cells. Since this effect of IL-2/IL-6 supplementation can be reproduced with the addition of Toll-like receptor agonists, it may be possible to exploit this mechanism and design new vaccines to improve the CD8 T cell response to influenza vaccination in older adults.

show abstract

“…Previously in vitro , we found that IL-6 produced during cognate interactions between CD4 T cells and dendritic cells enhanced expression of the anti-apoptotic molecule Bcl2 in the responding T cells (53). We did not observe changes in Bcl2 expression by 2° effectors responding against IAV in the presence or absence of IL-6 (not shown), but this does not rule out that regulation by IL-6 of other pro- or anti-apoptotic molecules plays a role in maximizing the recall CD4 T cell response.…”

Section: Discussionmentioning

confidence: 96%

Direct IL-6 Signals Maximize Protective Secondary CD4 T Cell Responses against Influenza

Strutt

McKinstry

Kuang

et al. 2016

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Memory T cells can often respond against pathogens that have evaded neutralizing antibodies and are thus key to vaccine-induced protection, yet the signals needed to optimize their responses are unclear. Here, we identify a dramatic and selective requirement for IL-6 to achieve optimal memory CD4 T cell recall following heterosubtypic influenza A virus (IAV) challenge of mice primed previously with wild-type or attenuated IAV strains. Through analysis of endogenous T cell responses and adoptive transfer of IAV-specific memory T cell populations, we find that without IL-6, CD4+, but not CD8+, secondary effector populations expand less and have blunted function and anti-viral impact. Early and direct IL-6 signals to memory CD4 T cells are required to program maximal secondary effector responses at the site of infection during heterosubtypic challenge indicating a novel role for a costimulatory cytokine in recall responses.

show abstract

TLR-Activated Dendritic Cells Enhance the Response of Aged Naive CD4 T Cells via an IL-6–Dependent Mechanism

Abstract: Material Supplementary 6.DC1http://www.jimmunol.org/content/suppl/2010/10/28/jimmunol.090129References

Cited by 46 publications

References 65 publications

Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice

Dysregulation of Toll-Like Receptor 7 Compromises Innate and Adaptive T Cell Responses and Host Resistance to an Attenuated West Nile Virus Infection in Old Mice

IL-2 and IL-6 cooperate to enhance the generation of influenza-specific CD8 T cells responding to live influenza virus in aged mice and humans

Direct IL-6 Signals Maximize Protective Secondary CD4 T Cell Responses against Influenza

Contact Info

Product

Resources

About