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

Strutt, Tara M.; McKinstry, K. Kai; Kuang, Yi; Finn, Caroline; Hwang, Ji Hae; Dhume, Kunal; Sell, Stewart; Swain, Susan L.

doi:10.4049/jimmunol.1600033

Cited by 16 publications

(18 citation statements)

References 60 publications

(80 reference statements)

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“…In viral infection models, IL‐6‐mediated enhancement of expansion and functional memory formation of T cells were also reported to exert immune‐stimulatory effects . However, a functional relevance of IL‐6 in the memory formation of tumor‐specific T‐cell responses remains to be elucidated, and thereby further intensive investigations on this subject will be required.…”

Section: Inflammation‐prone Environments Tend To Be Immune‐suppressivementioning

confidence: 99%

“…53 In viral infection models, IL-6-mediated enhancement of expansion and functional memory formation of T cells were also reported to exert immune-stimulatory effects. 54,55 However, a functional relevance of IL-6 in the memory formation of tumor-specific T-cell responses remains to be elucidated, and thereby further intensive investigations on this subject will be required. It is noteworthy that viral infection-induced early IL-6 production is a part of acute inflammation with robust up-regulation of various other cytokines F I G U R E 3 Transcription factor c-Maf dampens the anti-tumor activity of CD4 + T cells.…”

Section: Inflammation-pron E Environme Nts Tend To Be Immune-supprementioning

confidence: 99%

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Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

et al. 2017

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Accompanied by the growing clinical applications of immunotherapy in the treatment of cancer patients, development of novel therapeutic approaches to reverse the immune‐suppressive environment in cancer patients is eagerly anticipated, because the success of cancer immunotherapy is currently limited by immune‐suppressive effects in tumor‐bearing hosts. Interleukin (IL)‐6, a pleotropic proinflammatory cytokine, participates in tumor cell‐autonomous processes that are required for their survival and growth, and is therefore known as a poor prognostic factor in cancer patients. In addition, an emerging role of IL‐6 in modulating multiple functions of immune cells including T cells, dendritic cells, and macrophages is responsible for the dysfunction of innate and adaptive immunity against tumors. Therefore, the IL‐6‐targeting approach is of value as a promising strategy for desensitization and prevention of immune‐suppressive effects, and should be an effective treatment when combined with current immunotherapies. The aim of the present review is to discuss the immune‐suppressive aspects of IL‐6, notably with modification of T‐cell functions in cancer patients, and their relationship to anti‐tumor immune responses and cancer immunotherapy.

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Section: Inflammation‐prone Environments Tend To Be Immune‐suppressivementioning

confidence: 99%

Section: Inflammation-pron E Environme Nts Tend To Be Immune-supprementioning

confidence: 99%

Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

et al. 2017

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“…Elevated IL-6 is viewed as a distinctly proinflammatory cytokine, promptly activating the host defense system to perform diverse functions[ 17 ]. Early and direct IL-6 signals were involved in aiding immune responses at the site of infection during heterosubtypic challenge[ 18 ]. Some studies reported that IL-6 was a more suitable parameter in cases of severe systemic inflammation for patients with severe liver impairment than WBC or CRP[ 14 ].…”

Section: Discussionmentioning

confidence: 99%

High levels of serum interleukin-6 increase mortality of hepatitis B virus-associated acute-on-chronic liver failure

Zhou

Zhang

et al. 2020

WJG

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BACKGROUND Patients with hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) present a complex and poor prognosis. Systemic inflammation plays an important role in its pathogenesis, and interleukin-6 (IL-6) as a pro-inflammatory cytokine is related with severe liver impairment and also plays a role in promoting liver regeneration. Whether serum IL-6 influences HBV-ACLF prognosis has not been studied. AIM To determine the impact of serum IL-6 on outcome of patients with HBV-ACLF. METHODS We performed a retrospective study of 412 HBV-ACLF patients. The findings were analyzed with regard to mortality and the serum IL-6 level at baseline, as well as dynamic changes of serum IL-6 within 4 wk. RESULTS The serum IL-6 level was associated with mortality. Within 4 wk, deceased patients had significantly higher levels of IL-6 at baseline than surviving patients [17.9 (7.3-57.6) vs 10.4 (4.7-22.3), P = 0.011]. Patients with high IL-6 levels (> 11.8 pg/mL) had a higher mortality within 4 wk than those with low IL-6 levels (≤ 11.8 pg/mL) (24.2% vs 13.2%, P = 0.004). The odds ratios calculated using univariate and multivariate logistic regression were 2.10 (95% confidence interval [CI]: 1.26-3.51, P = 0.005) and 2.11 (95%CI: 1.15-3.90, P = 0.017), respectively. The mortality between weeks 5 and 8 in patients with high IL-6 levels at 4 wk was 15.0%, which was significantly higher than the 6.6% mortality rate in patients with low IL-6 levels at 4 wk (hazard ratio = 2.39, 95%CI: 1.05-5.41, P = 0.037). The mortality was 5.0% in patients with high IL-6 levels at baseline and low IL-6 levels at 4 wk, 7.5% in patients with low IL-6 levels both at baseline and at 4 wk, 11.5% in patients with low IL-6 levels at baseline and high IL-6 levels at 4 wk, and 16.7% in patients with high IL-6 levels both at baseline and at 4 wk. The increasing trend of the mortality rate with the dynamic changes of IL-6 was significant ( P for trend = 0.023). CONCLUSION A high level of serum IL-6 is an independent risk factor for mortality in patients with HBV-ACLF. Furthermore, a sustained high level or dynamic elevated level of serum IL-6 indicates a higher mortality.

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“…The antigen-specific regulation of inflammatory responses provides an additional means by which the immune response can generate alarm signals during infections with pathogens that possess means to evade detection by the innate immune-sensing mechanisms discussed earlier [ 136 ]. It also provides a means whereby experienced memory cells can modulate the effector functions of the ensuing adaptive response of expanded secondary effector T cells that arise from resting memory T cell precursors during recall [ 137 ].…”

Section: Inflammation and The Generation Of Adaptive Immune Responmentioning

confidence: 99%

“…Following secondary IAV infection, the earlier and more robust inflammatory response induced by memory CD4 T cells correlates with improved control of the virus in the lung [ 133 ]. Our recent findings show that one innate inflammatory cytokine involved in this response, IL-6, plays a central role in maximizing the multicytokine-producing potential of secondary CD4 + T effector cells that accumulate in the lung at the peak of the recall response [ 137 ] ( Figure 2 ). In murine and human systems, multicytokine-producing potential, or the ability to coproduce TNF, IL-2, and IFN- γ , is associated with the ability of memory T cell responses to protect against numerous viral, bacterial, and parasitic pathogens [ 120 ].…”

Section: Inflammation and The Generation Of Adaptive Immune Responmentioning

confidence: 99%

The Regulation of Inflammation by Innate and Adaptive Lymphocytes

Cronkite

Strutt

2018

Journal of Immunology Research

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150

107

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Inflammation plays an essential role in the control of pathogens and in shaping the ensuing adaptive immune responses. Traditionally, innate immunity has been described as a rapid response triggered through generic and nonspecific means that by definition lacks the ability to remember. Recently, it has become clear that some innate immune cells are epigenetically reprogrammed or “imprinted” by past experiences. These “trained” innate immune cells display altered inflammatory responses upon subsequent pathogen encounter. Remembrance of past pathogen encounters has classically been attributed to cohorts of antigen-specific memory T and B cells following the resolution of infection. During recall responses, memory T and B cells quickly respond by proliferating, producing effector cytokines, and performing various effector functions. An often-overlooked effector function of memory CD4 and CD8 T cells is the promotion of an inflammatory milieu at the initial site of infection that mirrors the primary encounter. This memory-conditioned inflammatory response, in conjunction with other secondary effector T cell functions, results in better control and more rapid resolution of both infection and the associated tissue pathology. Recent advancements in our understanding of inflammatory triggers, imprinting of the innate immune responses, and the role of T cell memory in regulating inflammation are discussed.

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

Cited by 16 publications

References 60 publications

Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

High levels of serum interleukin-6 increase mortality of hepatitis B virus-associated acute-on-chronic liver failure

The Regulation of Inflammation by Innate and Adaptive Lymphocytes

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