Introduction to immune cell signalling

The dynamic interaction of cells of the immune system with other cells, antigens and secreted factors determines the nature of an immune response. The response of individual cells is governed by the sequence of intracellular signalling events triggered following the association of cell surface molecules during cell-cell contact or the detection of soluble molecules of host or pathogen origin. In this review we will first outline the general principles of intracellular signal transduction. We will then describe the signalling pathways triggered following the recognition of antigen, as well as the detection of cytokines, and discuss how the signalling pathways activated regulate the effector response.

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Tribbles: ‘puzzling’ regulators of cell signalling

Biochemical Society Transactions ◽

10.1042/bst0390684 ◽

2011 ◽

Vol 39 (2) ◽

pp. 684-687 ◽

Cited By ~ 24

Author(s):

Endre Kiss-Toth

Keyword(s):

Signal Transduction ◽

Transcription Factors ◽

Cell Signalling ◽

Life Forms ◽

Signalling Pathways ◽

Fundamental Feature ◽

Extracellular Signals ◽

Recent Developments ◽

Intracellular Signal ◽

Signal Transduction Systems

Sensing and interpreting extracellular signals in response to changes in the environment has been a fundamental feature of all life forms from the very beginning of evolution. To fulfil this function, networks of proteins have evolved, forming the intracellular signal transduction machinery. Whereas the appropriate control of these signal transduction systems is essential to homoeostasis, dysregulation of signalling leads to disease and often the death of the organism. The tribbles family of pseudokinases have emerged in recent years as key controllers of signal transduction via their interactions with several key kinases, ubiquitin ligases and transcription factors. In line with their role in regulating fundamentally important signalling pathways, members of the tribbles family have been implicated in the development of a range of human diseases. Whereas our mechanistic understanding of how these proteins contribute to disease is far from complete, the present paper attempts to summarize some of the most important recent developments in this field of research.

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Dugbe virus ovarian tumour domain interferes with ubiquitin/ISG15-regulated innate immune cell signalling

Journal of General Virology ◽

10.1099/vir.0.048322-0 ◽

2013 ◽

Vol 94 (2) ◽

pp. 298-307 ◽

Cited By ~ 16

Author(s):

S. Bakshi ◽

B. Holzer ◽

A. Bridgen ◽

G. McMullan ◽

D. G. Quinn ◽

...

Keyword(s):

Immune Cell ◽

Cell Signalling ◽

Ovarian Tumour ◽

Enzymic Activity ◽

Catalytic Site ◽

Signalling Pathways ◽

Block Type ◽

Type I ◽

L Protein ◽

Tnf Α

The ovarian tumour (OTU) domain of the nairovirus L protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. We have confirmed that the OTU domain from the L protein of the apathogenic nairovirus Dugbe virus has deubiquitinating and deISGylating activity and shown that, when expressed in cells, it is highly effective at blocking the TNF-α/NF-κB and interferon/JAK/STAT signalling pathways even at low doses. Point mutations of the catalytic site of the OTU [C40A, H151A and a double mutant] both abolished the ability of the OTU domain to deubiquitinate and deISGylate proteins and greatly reduced its effect on cell signalling pathways, confirming that it is this enzymic activity that is responsible for blocking the two signalling pathways. Expression of the inactive mutants at high levels could still block signalling, suggesting that the viral OTU can still bind to its substrate even when mutated at its catalytic site. The nairovirus L protein is a very large protein that is normally confined to the cytoplasm, where the virus replicates. When the OTU domain was prevented from entering the nucleus by expressing it as part of the N-terminal 205 kDa of the viral L protein, it continued to block type I interferon signalling, but no longer blocked the TNF-α-induced activation of NF-κB.

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Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis

Cells ◽

10.3390/cells10113116 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3116

Author(s):

Tobias Moser ◽

Lena Hoepner ◽

Kerstin Schwenker ◽

Michael Seiberl ◽

Julia Feige ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

B Cells ◽

Cell Surface ◽

Mode Of Action ◽

Immune Cell ◽

Cell Surface Molecules ◽

Surface Molecules ◽

Surface Patterns ◽

The Impact

Cladribine (CLAD) is a deoxyadenosine analogue prodrug which is given in multiple sclerosis (MS) as two short oral treatment courses 12 months apart. Reconstitution of adaptive immune function following selective immune cell depletion is the presumed mode of action. In this exploratory study, we investigated the impact of CLAD tablets on immune cell surface molecules for adhesion (CAMs) and costimulation (CoSs) in people with MS (pwMS). We studied 18 pwMS who started treatment with CLAD and 10 healthy controls (HCs). Peripheral blood mononuclear cells were collected at baseline and every 3 months throughout a 24-month period. We analysed ICAM-1, LFA-1, CD28, HLADR, CD154, CD44, VLA-4 (CD49d/CD29), PSGL-1 and PD-1 with regard to their expression on B and T cells (T helper (Th) and cytotoxic T cells (cT)) and surface density (mean fluorescence intensity, MFI) by flow cytometry. The targeted analysis of CAM and CoS on the surface of immune cells in pwMS revealed a higher percentage of ICAM-1 (B cells, Th, cT), LFA-1 (B cells, cT), HLADR (B cells, cT), CD28 (cT) and CD154 (Th). In pwMS, we found lower frequencies of Th and cT cells expressing PSGL-1 and B cells for the inhibitory signal PD-1, whereas the surface expression of LFA-1 on cT and of HLADR on B cells was denser. Twenty-four months after the first CLAD cycle, the frequencies of B cells expressing CD44, CD29 and CD49d were lower compared with the baseline, together with decreased densities of ICAM-1, CD44 and HLADR. The rate of CD154 expressing Th cells dropped at 12 months. For cT, no changes were seen for frequency or density. Immune reconstitution by oral CLAD was associated with modification of the pro-migratory and -inflammatory surface patterns of CAMs and CoSs in immune cell subsets. This observation pertains primarily to B cells, which are key cells underlying MS pathogenesis.

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