The role of γδ T cells in airway epithelial injury and bronchial responsiveness after chlorine gas exposure in mice

Koohsari, Hossein; Tamaoka, Meiyo; Campbell, Holly R.; Martin, James G.

doi:10.1186/1465-9921-8-21

Cited by 37 publications

(32 citation statements)

References 26 publications

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“…Macrophages and DCs can recognize non-self structures such as pathogen-associated molecular patterns (PAMPs) by pattern recognition receptor (PRR) such as Toll-like receptors (TLRs) (16). More recent studies strongly emphasize the innate features and functions of ␥␦ T cells, including the participation in wound healing (17), tissue repair (18), and the ability to present antigen (19 -20). Previously, we have used CDR3 peptide as probe to pan twelve peptide libraries.…”

Section: Discussionmentioning

confidence: 99%

Antigen Specificity of γδ T Cells Depends Primarily on the Flanking Sequences of CDR3δ

Xi¹,

Guo²,

Chen

et al. 2009

Journal of Biological Chemistry

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The structural basis that determines the specificity of ␥␦ T cell receptor (TCR) recognition remains undefined. Our previous data show that the complementary determining region of human TCR␦ (CDR3␦) is critical to ligand binding. Here we used linear and configurational approaches to examine the roles of V, N-D-N, or J regions in CDR3␦-mediated antigen recognition. Surprisingly, we found that the binding activities of CDR3␦ from different ␥␦ TCRs to their target tissues and ligands depend on the conserved flanking sequences (V and J) but not as much on the D region of CDR3␦ fragment. We further defined the key residues in the V and J regions of CDR3␦ fragments, including the cysteine residue in the V fragment and the leucine residue in the J fragment that determine their ligand binding specificity. Our results demonstrate that TCR␦ primarily uses conserved flanking regions to bind ligands. This finding may provide an explanation for the limited number of ␥␦ TCR ligands that have as yet been identified.Extensive studies suggest that ␥␦ T cells play important roles in host defense against microbial infections, monitoring of tumorigenesis, immunoregulation, and development of autoimmunity (1-3). However, little is known about the structural basis of antigenic recognition by ␥␦ T cell receptor (TCR) 3 because of the limited identified specific ligands for ␥␦ TCR and the lack of structural information revealing how ␥␦ TCR might interact with such ligands.The crystallographic structure of a murine ␥␦ TCR in complex with major histocompatibility complex class (MHC) Ib T22 (4, 5) showed that the CDR loops f ␥␦ TCR, predominantly germline-encoded residues of the complementary determining region of human TCR␦ (CDR3␦), are in direct contact with T22, suggesting that the primary sequence of CDR3 in ␥␦ TCR, especially CDR3␦, serves as a key determinant for the specificity of antigen recognition. Our recent finding that CDR3␦ peptide mimics human ␥␦ TCR binding to tumor cells and tissues is consistent with the role of CDR3␦ in ␥␦ TCR recognition (6).Based on this finding, we used synthesized CDR3␦ peptide as a probe to screen putative protein ligands in tumor protein extracts by affinity chromatography analysis. With this novel strategy, we have successfully identified seven tumor-related epitopes, two hepatitis B virus (HBV) infection-related antigenic epitopes, and two self proteins including heat shock protein (HSP) 60 and human mutS homolog 2 (hMSH2) that are recognized by human ␥␦ TCR (7). These results further support that the primary sequence of CDR3␦ in ␥␦ TCR determine the specificity of antigen binding.CDR3␦ is composed of fragments derived from V, N-D-N, and J gene segments. The flanking sequences composed of V and J fragment is conserved while N-D-N region is diverse. The diversity of ␥␦ TCRs is supposedly higher than that of TCR␣␤ due to the link of D gene fragment and the insertion of nucleotide acids (8). However, the number of identified antigenic ligands recognized by ␥␦ TCR remains very limited. It has been d...

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Section: Discussionmentioning

confidence: 99%

Antigen Specificity of γδ T Cells Depends Primarily on the Flanking Sequences of CDR3δ

Xi¹,

Guo²,

Chen

et al. 2009

Journal of Biological Chemistry

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“…There is also evidence that they may have a role in the airways, although they are less numerous there than in the aforementioned tissues. It appears that chlorine causes more airway injury in gd-T cell-deficient mice (42). Following chlorine exposure, the numbers of epithelial cells in the BALF of mice that are deficient in gd-T cell receptor is greater than in wild-type animals (42).…”

Section: Animal Models Of Chlorine-induced Lung Injurymentioning

confidence: 99%

“…It appears that chlorine causes more airway injury in gd-T cell-deficient mice (42). Following chlorine exposure, the numbers of epithelial cells in the BALF of mice that are deficient in gd-T cell receptor is greater than in wild-type animals (42). The inflammatory response to chlorine exposure is delayed in the gd 2/2 mice, and the change in airway responsiveness to methacholine is also diminished.…”

Section: Animal Models Of Chlorine-induced Lung Injurymentioning

confidence: 99%

Chlorine Gas Inhalation: Human Clinical Evidence of Toxicity and Experience in Animal Models

White¹,

Martin²

2010

Proceedings of the American Thoracic Society

272

211

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“…19 Interestingly, patients with IPF have decreased ␥␦ T cells in their bronchoalveolar lavage (BAL) fluid. 20 In lung injury models, such as chlorine gas 21 or ozone, 22 ␥␦ T cells are required for neutrophil influx and epithelial repair. Furthermore, ␥␦ T-cell populations increase in response to bleomycin injury.…”

mentioning

confidence: 99%

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Pociask

Chen

Choi

et al. 2011

The American Journal of Pathology

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␥␦ T cells are a subset of T cells associated with epithelial mucosal tissues and play a prominent role in both promoting and dampening inflammatory responses to pathogens; in addition, they strongly mediate epithelial repair. By using a bleomycin model of pulmonary fibrosis, we found that ␥␦ T-cell populations dramatically increased after bleomycin administration. To determine the importance of these cells, we exposed mice lacking the ␦ chain of the ␥␦ T-cell receptor (␥␦ knockout [KO]) to bleomycin. Pulmonary fibrosis was more severe in ␥␦ KO mice, as measured by collagen deposition (hydroxyproline) and histopathological features. Furthermore, there was no evidence of resolution of the fibrotic response up to 45 days after bleomycin therapy. In contrast to control mice, ␥␦ KO mice had decreased concentrations of IL-6, granulocyte colony stimulating factor, chemokine CXC ligand (CXCL) 1, and interferon inducible protein 10/CXCL10. In vitro culture of ␥␦ T cells purified from lungs 17 days after bleomycin exposure (a time of peak influx of these cells) demonstrated that ␥␦ T cells produced substantial quantities of all four of these cytokines, suggesting that ␥␦ T cells are a predominant source of these proteins. To demonstrate that ␥␦ T cells are effector cells in the fibrotic response, we performed adoptive transfer experiments with ␥␦ T cells sorted from bleomycin-treated lungs; these cells were sufficient to resolve fibrosis in ␥␦ KO mice and restore CXCL10 levels comparable to wild-type mice. Furthermore, overexpression of CXCL10 in the lung decreased the severity of fibrosis seen in the ␥␦ KO mice. Finally, adoptive transfer of ␥␦ T cells from CXCL10 ؊/؊ mice failed to reverse the severe fibrosis in ␥␦ KO mice. These results indicate that ␥␦ T cells promote the resolution of fibrosis through the production of

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The role of γδ T cells in airway epithelial injury and bronchial responsiveness after chlorine gas exposure in mice

Abstract: Background: Acute exposure to chlorine (Cl 2 ) gas causes epithelial injury and airway dysfunction. γδ T cells are present in the mucosal surface of the airways and may contribute to the injury/repair

Cited by 37 publications

References 26 publications

Antigen Specificity of γδ T Cells Depends Primarily on the Flanking Sequences of CDR3δ

Antigen Specificity of γδ T Cells Depends Primarily on the Flanking Sequences of CDR3δ

Chlorine Gas Inhalation: Human Clinical Evidence of Toxicity and Experience in Animal Models

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

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