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The Role of Human Genetics in HIV-1 Infection
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Maureen P. Martin, Mary Carrington
The CCR5 gene has been mapped to the short arm of chromosome 3 within a chemokine receptor gene cluster that includes CCR1, CCR2, CCR3, CCR4, CCR6, CCR8, and CX3CR1 (58–60). The CCR5 gene became an obvious disease gene candidate for HIV-1 infection upon the discovery of CCR5 as a co-receptor for HIV-1 and screening the coding region of the gene was easily performed since it contains a single open reading frame (exon 4) of only 1,055 base pairs. A common, severe mutation characterized by a 32 base pair deletion, CCR5-Δ32, was rapidly identified (8–10). The deletion begins in the region encoding the third extracellular domain of CCR5, and results in a frame shift and premature stop codon in the fifth transmembrane domain. The truncated protein product is not expressed on the cell surface (9), explaining the nearly complete protection against HIV-1 infection (see Table 1), despite repeated exposures, in individuals homozygous for the mutant allele (8–10,61,62). Accordingly, peripheral blood lymphocytes (PBLs) from individuals homozygous for CCR5-Δ32 are resistant to infection with R5 (but not X4) strains of HIV-1 in vitro (9,10,63,64). The normal CCR5 function appears to be dispensable, perhaps because of the redundancy of the chemokine receptor system, since individuals who are homozygous for the CCR5-Δ32 are generally unremarkable (see Chapter 10).
Pathophysiology of Atopic Dermatitis and Atopiform Dermatitis
Published in Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld, Atopic Dermatitis and Eczematous Disorders, 2014
Thus IL-4, the prototypic Th2 cytokine, seemed to play a major role. This also proved to be true for other Th2 cytokines such as IL-5 and IL-13. Whereas IL-4 mRNA was prominent in acute AD lesions, chronic AD skin lesions had significantly fewer IL-4 mRNA-expressing cells but significantly greater IL-5 mRNA expression, most of it by T cells (Hamid et al. 1994). Thus, initiation of acute skin inflammation seemed to be associated with a predominance of IL-4 expression whereas maintenance of chronic inflammation was mostly associated with increased IL-5 expression and eosinophil infiltration (Hamid et al. 1994). Interestingly, recent work in a mouse model of AD suggests that accumulation of IL-5-producing Th2 cells and eosinophilic infiltration of the skin is mediated by interactions between the chemokine receptor CCR8 and its ligands (Debes and Diehl 2011, Islam et al. 2011).
TGF-β-induced CCR8 promoted macrophage transdifferentiation into myofibroblast-like cells
Published in Experimental Lung Research, 2022
Haijun Liu, Qingzhou Guan, Peng Zhao, Jiansheng Li
Chemokine receptor 8 (CCR8), a G-protein-coupled receptor (GPCR), is expressed in monocytes and T lymphocytes and is the specific receptor of human CC chemokine CCL1 and viral mononuclear inflammatory proteins (vCCL1).11 CCR8 could be selectively induced to regulate the cell activation and migration in antigen-activated neutrophils.12 CCR8 participates in the migration of monocytes to lymphatic vessels, and these monocytes can acquire the characteristics of dendritic cell in draining lymph nodes. However, the monocytes with defective CCR8 reside in the corresponding tissue and do not exhibit the properties of dendritic cells.13 Research has shown that expression of CCR8 on hepatic macrophages showed a significant functional involvement in the progression of hepatic fibrosis through promoting the migration of macrophages into the liver.14
The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study
Published in Pediatric Hematology and Oncology, 2019
Rebecca Ronsley, Amina Kariminia, Bernard Ng, Sara Mostafavi, Gregor Reid, Peter Subrt, Nobuko Hijiya, Kirk R. Schultz
Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and murine peritoneal macrophages.33 Moreover, it appears to be important as a check point inhibitor.34 There appears to be cross talk between signaling pathways downstream of CCR8 and TLR-4 resulting in cytokine production by murine macrophages.34,35 One group has described in that human IL-9-producing TH cells express the chemokine receptors CCR4 and CCR8, produce high levels of IL-5 and IL-13 resulting in down-regulation of TH2 cytokines.36 Moreover, there is unique subset of CCR8 + CD4 + FOXp3+ regulatory T cells (Treg) that are major drivers of immune regulation in the tumor environment.37 Thus, it appears that GNKG168 inhibits check point inhibition through the CCR8 Treg populations shown to be important in breast, colon, and lung cancers.38
Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8
Published in Journal of Extracellular Vesicles, 2018
Jordi Berenguer, Tonny Lagerweij, Xi Wen Zhao, Sophie Dusoswa, Petra van der Stoop, Bart Westerman, Mark C. de Gooijer, Marloes Zoetemelk, Anoek Zomer, Matheus H. W. Crommentuijn, Laurine E. Wedekind, Àlan López-López, Alberta Giovanazzi, Marina Bruch-Oms, Ida H. van der Meulen-Muileman, Rogier M. Reijmers, Toin H. van Kuppevelt, Juan-Jesús García-Vallejo, Yvette van Kooyk, Bakhos A. Tannous, Pieter Wesseling, Danijela Koppers-Lalic, W. Peter Vandertop, David P. Noske, Victor W. van Beusechem, Jacco van Rheenen, D. Michiel Pegtel, Olaf van Tellingen, Thomas Wurdinger
GBM is the most common primary malignant tumour of the central nervous system in adults and known to release large amounts of EVs [10,35,36]. Affected patients have an extremely poor prognosis with a median survival of only 15 months following treatment [37]. Standard of care currently consists of tumour resection combined with radiotherapy and concomitant and adjuvant chemotherapy with the alkylating agent temozolomide (TMZ). Although tumours may initially respond to this regimen, recurrences are inevitable and occur even while patients are still receiving adjuvant TMZ [38]. Here, we show that GBM EVs are inducers of cell proliferation and are capable of triggering TMZ resistance in recipient GBM cells. Using RNAi screening, we identified the chemokine (C-C motif) receptor 8 (CCR8) as a receptor for EVs. CCR8 is known to be expressed by T-helper 2 lymphocytes, natural killer cells, and monocytes. In the central nervous system (CNS), CCR8 expression is associated with phagocytic macrophages and activated microglial cells [39]. We demonstrate that CCR8 is also expressed on tumour cells and this CCR8 allows binding and entry of EVs via interaction of EV-bound glycans with the chemokine (C-C motif) ligand 18 (CCL18).