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. 2005 Nov;64(Suppl 4):iv70–iv76. doi: 10.1136/ard.2005.042523

What does tumour necrosis factor excess do to the immune system long term?

J Clark, P Vagenas, M Panesar, A Cope
PMCID: PMC1766919  PMID: 16239393

Abstract

Members of the tumour necrosis factor (TNF)/TNF-receptor (TNF-R) superfamily coordinate the immune response at multiple levels. For example, TNF, LTα, LTß and RANKL provide signals required for lymphoid neogenesis, CD27, OX-40, 4-1BB and CD30 deliver costimulatory signals to augment immune responses, while pro-apoptotic members such as TNF, CD95L and TRAIL may contribute to the termination of the response. Biological identity of individual family members has been revealed through studies of gain of function or gene deficient mutants. Most notable are the development of spontaneous inflammatory polyarthritis in human TNF-globin transgenic mice, the auto-inflammatory syndromes resulting from mutations in the 55-kDa TNF-R, and, in particular, the obligatory role for the RANKL/RANK axis in osteoclastogenesis and bone remodelling. A growing appreciation of the molecular basis of signalling pathways transduced by TNF-R has provided a framework for better understanding the biology of this expanding family. For while the rapid and robust activation of NF-κB and MAPK pathways is typical of acute TNF-R engagement, the molecular basis of sustained receptor signalling remains a mystery, in spite of its relevance to chronic inflammatory and immune responses. Focusing on T cells, this report describes some of the molecular footprints of sustained TNF-R engagement and illustrates how these may influence immune function. A common theme arising is that prolonged TNF stimulation alters signalling thresholds over time. The authors propose that one major outcome of long term exposure to TNF is a state of localised IL-2 deficiency at sites of inflammation. The implications of this deficiency are discussed.

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Figure 1.

Figure 1

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 Signalling footprints of the TNF/TNF-R superfamily. Prototype signalling modules recruited to death domain expressing TNF-R family members, including TNF-R1. Each pathway is associated with specific functions, but does not signal in isolation. AP, activator protein; ERK, extracellular regulating kinase; FADD, Fas associated death domain protein; IKK, IκB kinase; JNK, Jun N-terminal kinase; MEKK, MAP/ERK kinase kinase; MKK, MAP kinase kinase; NF-κB, nuclear factor kappa B; RIP, receptor-interacting protein; TRADD, TNF receptor-associated death domain protein; TRAF, TNF receptor-associated factor.

Figure 2.

Figure 2

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 (A) A signalling footprint for acute tumour necrosis factor. For TNF-R1 activation of NF-κB leads to a programme of gene transcription which includes antiapoptotic genes. In primary cells, the default response to TNF favours NF-κB over caspase activation. (B) A signalling footprint for chronic TNF. Here, attenuation of apoptotic pathways is maintained, while NF-κB dependent attenuation of reactive oxidative species (ROS) production enhances mitogen activated protein kinase phosphatase (MKP) activity thereby suppressing activation of JNK. For abbreviations see Figure l legend.

Figure 3.

Figure 3

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 TNF – a potent immunomodulator of adaptive immunity. Like other costimulatory TNF-R superfamily members, acute TNF exposure can enhance antigen specific responses. As the immune response evolves, sustained expression of TNF plays a non-redundant role in resolution of adaptive immunity. However, this may lead to sustained reactivity of T cells to self-antigens and an increased predisposition to autoimmunity.

Figure 4.

Figure 4

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 Tumour necrosis factor (TNF) regulates the switch from "antigen mode" to "inflammation mode" during terminal T cell differentiation. This model proposes that during the evolution of immune responses, CD4+ T cells become progressively refractory to T cell receptor (TCR) engagement. At the same time, cytokine signals may promote a unique gene expression signature favouring cell survival, migration, and effector responses. This change in thresholds of activation of signalling pathways will also lead to a state of relative interleukin (IL)-2 deficiency at sites of inflammation, with implications for maintaining immune homoeostasis. DC, dendritic cell; Teff, T effector cell.

Selected References

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