Spatial regulation of IL-4 signalling in vivo

Redpath, Stephen A.; Heieis, Graham A.; Perona-Wright, Georgia

doi:10.1016/j.cyto.2015.02.026

Cited by 22 publications

(17 citation statements)

References 106 publications

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“…Although they share low amino acid sequence identity, eg 23% in humans and 22% in cow, IL-4 and IL-13 are indeed closely related. They sit side by side in the mammalian genome and form part of a contiguous gene cluster sharing regulatory elements, and are frequently activated together as part of the same immune response [ 1 , 9 - 10 ]. They function not only in the immune system but also in pregnancy, fetal development, mammary development and lactation, and in higher brain functions including memory and learning in mammals [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

First in-depth analysis of the novel Th2-type cytokines in salmonid fish reveals distinct patterns of expression and modulation but overlapping bioactivities

et al. 2016

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IL-4 and IL-13 are closely related canonical type-2 cytokines in mammals and have overlapping bioactivities via shared receptors. They are frequently activated together as part of the same immune response and are the signature cytokines produced by T-helper (Th)2 cells and type-2 innate lymphoid cells (ILC2), mediating immunity against extracellular pathogens. Little is known about the origin of type-2 responses, and whether they were an essential component of the early adaptive immune system that gave a fitness advantage by limiting collateral damage caused by metazoan parasites. Two evolutionary related type-2 cytokines, IL-4/13A and IL-4/13B, have been identified recently in several teleost fish that likely arose by duplication of an ancestral IL-4/13 gene as a consequence of a whole genome duplication event that occurred at the base of this lineage. However, studies of their comparative expression levels are largely missing and bioactivity analysis has been limited to IL-4/13A in zebrafish. Through interrogation of the recently released salmonid genomes, species in which an additional whole genome duplication event has occurred, four genomic IL-4/13 loci have been identified leading to the cloning of three active genes, IL-4/13A, IL-4/13B1 and IL-4/13B2, in both rainbow trout and Atlantic salmon. Comparative expression analysis by real-time PCR in rainbow trout revealed that the IL-4/13A expression is broad and high constitutively but less responsive to pathogen-associated molecular patterns (PAMPs) and pathogen challenge. In contrast, the expression of IL-4/13B1 and IL-4/13B2 is low constitutively but is highly induced by viral haemorrhagic septicaemia virus (VHSH) infection and during proliferative kidney disease (PKD) in vivo, and by formalin-killed bacteria, PAMPs, the T cell mitogen PHA, and the T-cell cytokines IL-2 and IL-21 in vitro. Moreover, bioactive recombinant cytokines of both IL-4/13A and B were produced and found to have shared but also distinct bioactivities. Both cytokines rapidly induce the gene expression of antimicrobial peptides and acute phase proteins, providing an effector mechanism of fish type-2 cytokines in immunity. They are anti-inflammatory via up-regulation of IL-10 and down-regulation of IL-1β and IFN-γ. They modulate the expression of cellular markers of T cells, macrophages and B cells, the receptors of IFN-γ, the IL-6 cytokine family and their own potential receptors, suggesting multiple target cells and important roles of fish type-2 cytokines in the piscine cytokine network. Furthermore both cytokines increased the number of IgM secreting B cells but had no effects on the proliferation of IgM+ B cells in vitro. Taken as a whole, fish IL-4/13A may provide a basal level of type-2 immunity whilst IL-4/13B, when activated, provides an enhanced type-2 immunity, which may have an important role in specific cell-mediated immunity. To our knowledge this is the first in-depth analysis of the expression, modulation and bioactivities of type-2 cytokines in the same fish species, and...

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Section: Introductionmentioning

confidence: 99%

First in-depth analysis of the novel Th2-type cytokines in salmonid fish reveals distinct patterns of expression and modulation but overlapping bioactivities

et al. 2016

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“…The production of IL‐4 in the lymph node during H. polygyrus infection is likely to expose both CD11b + and CD11b − DCs to IL‐4 signals , and we show IL‐4Rα expression on the surface of both subsets of DCs. That CD11b − DCs did not become alternatively activated during helminth infection is further evidence of functional distinction between DC subsets.…”

Section: Discussionmentioning

confidence: 54%

Functional specialization of intestinal dendritic cell subsets during Th2 helminth infection in mice

et al. 2017

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Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) are professional antigen presenting cells, essential for the initiation of adaptive immune responses. Heterogeneous DC populations exist, and different subsets have been associated with the development of discrete T-helper (Th) cell responses. In the spleen, CD8α + DCs were reported to secrete high levels of IL-12p70 and preferentially induce Th1 responses, 88Stephen A. Redpath et al. Eur. J. Immunol. 2018. 48: 87-98 function under homeostatic conditions [3][4][5][6][7], but their contribution during infection is less well understood. Helminth parasites are common pathogens of the human intestinal tract, infecting some 2 billion people worldwide [8]. Helminths typically induce strong Th2 cell responses, characterized by the cytokines IL-4, , and DCs are essential to this process [10][11][12] (Fig. 1C).This reduction was accompanied by an increase in the proportion and number of these DCs in the MLN (Fig. 1D). These data support a hypothesis that CD11b + CD103 + DCs leave the infection site upon helminth infection, and accumulate in the local lymph node. The proportion and number of CD11b + CD103 − DCs in the MLN also increased following H. polygyrus infection (Fig. 1F), although the number of these DCs did not decrease significantly in the SI-LP (Fig. 1E). MHCII than in the SI-LP, but there were no differences in expression of MHCII, CD40 or OX40L between the three populations, neither in naïve nor infected animals (Supporting Information Fig. 3 and data not shown). Interestingly, CD11b + CD103 − and CD11b + CD103 + DCs in the MLN showed higher expression of PDL2 following H. polygyrus infection compared to DCs in naïve mice ( Fig. 2A and B). PDL2 expression on CD103 + CD11b − DCs was unaffected by infection, although this subset showed high basal expression ( Fig. 2A and B). Thus, in the MLN, only CD11b + DCs upregulate the co-stimulatory molecule PDL2 in response to H. polygyrus infection.To further examine the nature of DC subset activation in response to helminth infection, we assessed the cytokine expression of each population. IL-6 and IL-10 have previously been associated with Th2 development in response to helminth antigens [31,32]. We analyzed gene expression for the cytokines IL-6, IL-10 and the canonical Th1 polarizing signal, in Fig. 2A and B), both subsets are IRF4-dependent, and both share developmental origins [3,6]. Our sort gates are illustrated in Supporting Information Fig. 4. During H. polygyrus infection, CD11b + DCs expressed more il6 than CD11b − DCs (Fig. 2C). CD11b + DCs also expressed 2 fold more il10 than did CD11b − DCs (Fig. 2C). In contrast, il12p40and il12p35 gene expression was 3 fold higher in CD11b − than in CD11b + DCs (Fig. 2C) ( Fig. 5C). Control wells containing T cells and DCs without peptide antigen produced very little cytokine, irrespective of DC subset (Supporting Information Fig. 9 to become Th2-inducing. To tes...

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“…The characterisation of CD4 + and CD8 + resident memory T cells in the affected tissues has redefined our models of T cell memory (Carbone and Gebhardt, 2019). T cell cytokines are thought to be segregated by tissue, with IL-4 concentrated in the active lymph node and IL-5 and IL-13 dominating in the infected tissue (Liang et al, 2011;Redpath et al, 2015). Myeloid cells in the effector site are key to tissue remodelling, clearing of microorganisms and debris, and the initiation and perpetuation of appropriate T cell responses (Allen and Wynn, 2011;Kim and Kim, 2018;Rolot and Dewals, 2018).…”

Section: Discussionmentioning

confidence: 99%

Isolation and functional characterisation of lamina propria leukocytes from helminth-infected, murine small intestine

Webster

Andrusaite

Shergold

et al. 2019

Preprint

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The use of helminth infections as tools to understand the type 2 immune response is a well-established technique and important to many areas of immunological research. The phenotype and function of immune cell populations at the site of infection is a key determinant of pathogen clearance. However, infections with helminths such as the murine nematode Heligomosmoides polygryrus cause increased mucus production and thickening of the intestinal wall, which can result in extensive cell death when isolating and analysing cells from the lamina propria (LP). Populations of larger immune cells such as macrophages and dendritic cells are often trapped within mucus or dying tissues. Here we describe an optimised protocol for isolating LP leukocytes from the small intestine of H.polygyrus -infected mice, and we demonstrate phenotypic and functional identification of myeloid and CD4 + T cell subsets using cytokine staining and flow cytometry. Our protocol may provide a useful experimental method for the immunological analysis of the affected tissue site during helminth infections.

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Spatial regulation of IL-4 signalling in vivo

Cited by 22 publications

References 106 publications

First in-depth analysis of the novel Th2-type cytokines in salmonid fish reveals distinct patterns of expression and modulation but overlapping bioactivities

First in-depth analysis of the novel Th2-type cytokines in salmonid fish reveals distinct patterns of expression and modulation but overlapping bioactivities

Functional specialization of intestinal dendritic cell subsets during Th2 helminth infection in mice

Isolation and functional characterisation of lamina propria leukocytes from helminth-infected, murine small intestine

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