November 2020
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25 Reads
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November 2020
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25 Reads
July 1998
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239 Reads
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107 Citations
The Journal of Immunology
Although recent findings indicate that gamma delta T cells influence both early innate and Ag-specific adaptive host responses, it has remained unclear what triggers gamma delta T cell reactivity. Investigating very early T cell activation in mouse and human models of bacterial infection, we measured CD69 expression as an indicator of early cellular activation. Both murine alpha beta and gamma delta T cells responded polyclonally to systemic bacterial infections, and to LPS. However, gamma delta T cells responded more strongly to the bacteria and to LPS. In vitro LPS-stimulated human T cells showed a similar differential response pattern. We identified TNF-alpha as mediator of the early differential T cell activation, and of differential proliferative responses. The stronger response of gamma delta T cells to TNF-alpha was correlated with higher inducible expression levels of TNF-Rp75. Among unstimulated splenocytes, more gamma delta T cells than alpha beta T cells expressed CD44 at high levels. The data suggest that TNF-Rp75 determines the differential T cell reactivity, and that most gamma delta T cells in the normal spleen are present in a presensitized state. As TNF-alpha stimulates activated T cells, it may early preferentially connect gamma delta T cell functions with those of cells that produce this cytokine, including activated innate effector cells and Ag-stimulated T lymphocytes.
June 1998
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410 Reads
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22 Citations
The Journal of Immunology
Although recent findings indicate that γδ T cells influence both early innate and Ag-specific adaptive host responses, it has remained unclear what triggers γδ T cell reactivity. Investigating very early T cell activation in mouse and human models of bacterial infection, we measured CD69 expression as an indicator of early cellular activation. Both murine αβ and γδ T cells responded polyclonally to systemic bacterial infections, and to LPS. However, γδ T cells responded more strongly to the bacteria and to LPS. In vitro LPS-stimulated human T cells showed a similar differential response pattern. We identified TNF-α as mediator of the early differential T cell activation, and of differential proliferative responses. The stronger response of γδ T cells to TNF-α was correlated with higher inducible expression levels of TNF-Rp75. Among unstimulated splenocytes, more γδ T cells than αβ T cells expressed CD44 at high levels. The data suggest that TNF-Rp75 determines the differential T cell reactivity, and that most γδ T cells in the normal spleen are present in a presensitized state. As TNF-α stimulates activated T cells, it may early preferentially connect γδ T cell functions with those of cells that produce this cytokine, including activated innate effector cells and Ag-stimulated T lymphocytes.
September 1994
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20 Reads
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18 Citations
The Journal of Immunology
Mouse gamma delta T cell hybridomas from various strains that express a TCR-V gamma 1/V delta 6 respond weakly to an autologous Ag and more strongly to a short segment of the mycobacterial heat shock protein-60 (HSP-60). However, V gamma 1/V delta 6 hybridomas derived from AKR mice show greatly reduced or absent responses to these stimuli. To determine whether the lack of response in these AKR hybridomas is caused by polymorphisms found in the expressed AKR gamma and TCR-delta genes or, instead, stems from other genes in AKR, we crossed an AKR mouse with a responder mouse, C57BL/10 (B10), and prepared hybridomas from F1 progeny. Expression of an AKR V gamma 1-J gamma 4-C gamma 4 gene correlated with nonresponsiveness, whereas expression of a B10 V gamma 1-J gamma 4-C gamma 4 gene in most hybridomas ensured responses to both self Ag and the HSP-60 peptide. An allelic difference in the expressed V gamma 6 gene was irrelevant to these responses. Moreover, transfection of a functional B10 V gamma 1-J gamma 4-C gamma 4 gene into an F1 hybridoma variant that had lost the AKR version of this gene restored responses. The allelic gamma gene products differ at nine amino acids in the V region, and three amino acids in the C region. In addition, the AKR C gamma 4 region contains a 16-amino acid insertion. We propose that amino acid differences among those encoded by the AKR V gamma 1-J gamma 4-C gamma 4 gene are responsible for the lack of response, and reduce the ability of the TCR-gamma delta to bind the relevant Ag.
August 1994
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8 Citations
The Journal of Immunology
Mouse gamma delta T cell hybridomas from various strains that express a TCR-V gamma 1/V delta 6 respond weakly to an autologous Ag and more strongly to a short segment of the mycobacterial heat shock protein-60 (HSP-60). However, V gamma 1/V delta 6 hybridomas derived from AKR mice show greatly reduced or absent responses to these stimuli. To determine whether the lack of response in these AKR hybridomas is caused by polymorphisms found in the expressed AKR gamma and TCR-delta genes or, instead, stems from other genes in AKR, we crossed an AKR mouse with a responder mouse, C57BL/10 (B10), and prepared hybridomas from F1 progeny. Expression of an AKR V gamma 1-J gamma 4-C gamma 4 gene correlated with nonresponsiveness, whereas expression of a B10 V gamma 1-J gamma 4-C gamma 4 gene in most hybridomas ensured responses to both self Ag and the HSP-60 peptide. An allelic difference in the expressed V gamma 6 gene was irrelevant to these responses. Moreover, transfection of a functional B10 V gamma 1-J gamma 4-C gamma 4 gene into an F1 hybridoma variant that had lost the AKR version of this gene restored responses. The allelic gamma gene products differ at nine amino acids in the V region, and three amino acids in the C region. In addition, the AKR C gamma 4 region contains a 16-amino acid insertion. We propose that amino acid differences among those encoded by the AKR V gamma 1-J gamma 4-C gamma 4 gene are responsible for the lack of response, and reduce the ability of the TCR-gamma delta to bind the relevant Ag.
March 1994
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12 Reads
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50 Citations
The Journal of Immunology
Hybridomas representing the V gamma 1-positive subset of murine gamma delta T cells secrete lymphokines in response to synthetic peptides representing a short segment of the mycobacterial 60-kDa heat shock protein (HSP-60). Here we show the TCR dependency of this response by transfection of productively rearranged TCR genes derived from an HSP-60 reactive gamma delta T cell hybridoma. We also have defined structural requirements for the stimulatory peptide. The smallest HSP-60 peptide capable of stimulating these hybridomas is seven amino acids long, representing positions 181-187, and having the sequence FGLQLEL. Amino acid-substituted derivatives of this peptide, and another containing the same core, p180-190, revealed amino acids essential for stimulatory activity. Phenylalanine in position 181 and leucine in position 183 seem to be required for stimulation of all HSP-60 reactive cells, whereas others are only required by some. Clonal differences in the responses to these peptides provide indirect evidence for cognate TCR-peptide interactions. The smallest stimulatory peptide, p181-187, represents an area not well conserved among HSP-60 molecules of other species, and stimulates a mycobacteria-specific response unlike the earlier observed cross-reactive responses of the same hybridomas with longer HSP-60 peptides derived from mycobacteria and other species (our manuscript in preparation). We propose that the TCR-dependent multiclonal gamma delta T cell response to HSP-60 peptides and derivatives, which in some ways resembles superantigen responses and in other ways resembles responses to conventional Ag, may be a separate, third type of Ag response by T cells.
February 1994
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1 Read
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28 Citations
The Journal of Immunology
Hybridomas representing the V gamma 1-positive subset of murine gamma delta T cells secrete lymphokines in response to synthetic peptides representing a short segment of the mycobacterial 60-kDa heat shock protein (HSP-60). Here we show the TCR dependency of this response by transfection of productively rearranged TCR genes derived from an HSP-60 reactive gamma delta T cell hybridoma. We also have defined structural requirements for the stimulatory peptide. The smallest HSP-60 peptide capable of stimulating these hybridomas is seven amino acids long, representing positions 181-187, and having the sequence FGLQLEL. Amino acid-substituted derivatives of this peptide, and another containing the same core, p180-190, revealed amino acids essential for stimulatory activity. Phenylalanine in position 181 and leucine in position 183 seem to be required for stimulation of all HSP-60 reactive cells, whereas others are only required by some. Clonal differences in the responses to these peptides provide indirect evidence for cognate TCR-peptide interactions. The smallest stimulatory peptide, p181-187, represents an area not well conserved among HSP-60 molecules of other species, and stimulates a mycobacteria-specific response unlike the earlier observed cross-reactive responses of the same hybridomas with longer HSP-60 peptides derived from mycobacteria and other species (our manuscript in preparation). We propose that the TCR-dependent multiclonal gamma delta T cell response to HSP-60 peptides and derivatives, which in some ways resembles superantigen responses and in other ways resembles responses to conventional Ag, may be a separate, third type of Ag response by T cells.
December 1993
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81 Reads
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42 Citations
The Journal of Immunology
Murine V gamma 5 and V gamma 6+ T lymphocytes develop sequentially in the thymus during fetal and newborn life, giving rise to intraepithelial lymphocytes of the epidermis and female reproductive tract. In analyzing a panel of gamma delta T cell hybridomas derived from various tissues, we found that all V gamma 6+ cells tested (n = 25) expressed V gamma 5-C gamma 1 mRNA, whereas none of a panel of V gamma 6- cells analyzed (n = 33) expressed this mRNA. V gamma 6 mRNA was rare in V gamma 5+ cells (1 of 9), and absent in all other gamma delta T cells (n = 10). These findings suggest that most, if not all, V gamma 6-TCR+ lymphocytes arise from precursor cells that have previously rearranged the V gamma 5 gene, and indicate that V gamma 5 and V gamma 6+ lymphocytes belong to a common, distinct lineage that does not give rise to other gamma delta T cells.
November 1993
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1 Read
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27 Citations
The Journal of Immunology
Murine V gamma 5 and V gamma 6+ T lymphocytes develop sequentially in the thymus during fetal and newborn life, giving rise to intraepithelial lymphocytes of the epidermis and female reproductive tract. In analyzing a panel of gamma delta T cell hybridomas derived from various tissues, we found that all V gamma 6+ cells tested (n = 25) expressed V gamma 5-C gamma 1 mRNA, whereas none of a panel of V gamma 6- cells analyzed (n = 33) expressed this mRNA. V gamma 6 mRNA was rare in V gamma 5+ cells (1 of 9), and absent in all other gamma delta T cells (n = 10). These findings suggest that most, if not all, V gamma 6-TCR+ lymphocytes arise from precursor cells that have previously rearranged the V gamma 5 gene, and indicate that V gamma 5 and V gamma 6+ lymphocytes belong to a common, distinct lineage that does not give rise to other gamma delta T cells.
February 1992
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16 Reads
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3 Citations
Chemical Immunology
... As stated before, it is possible that cellular selection is V gene allele-specific. The finding that the reactivity of V␥1͞V␦6-expressing ␥␦ hybridomas to heat-shock proteinderived peptides depends on the V␥1-C␥4 allele agrees well with this notion (30). Similar V gene allele specificity has been shown to operate in the selection of ␣ T cells. ...
August 1994
The Journal of Immunology
... Intriguingly, these characteristics can also be observed in human lung DC isolated from patients with atopic asthma and may represent genuine features of mucosal inflammatory disorders (36). Vδ1 + T-cell-induced maturation of CD1 + myeloid DC does not rely on foreign antigen and is chiefly mediated by TNFα (35), which also triggers rapid activation of γδ T-cells (37)(38)(39), and likely enables timely immune responses to a barrier breach. Indeed, full DC maturation has long been known to require interaction with T-cells (40), but αβ T-cell clones with fine antigen specificity are rare in the periphery. ...
... Such a function was suggested for the Qa Ag by showing that it can present a hsp60 peptide (35) to V y l . l + y6 T cells (36). Using V y l . ...
February 1992
Chemical Immunology
... Interestingly, the majority of the insulin peptide reactive, Vγ1+ γδ T cell hybridomas in the NOD-derived collection (3/5), and one hybridoma expressing the very similar Vγ2 gene, shared a distinctive CDR3 motif in the junction of their rearranged γ genes (W-MR-S/T) [28]. We did not find the complete motif in any of a large number of C57BL/6, C57BL/10 or AKR/J-derived Vγ1+ hybridomas (0/96), although numerous cells contained a partial match [27,51,53,54]. Testing just one these cells -the B10-derived hybridoma 77BAS-12 containing a γ CDR3 with the sequence W-R-S -we found a peptide responder (Fig.7, panel D). ...
September 1994
The Journal of Immunology
... Interestingly, cellular stress can be perceived differently by the two main human γδ T-cell subtypes. While specific Vδ1 TCR ligands remain elusive, these cells are highly efficient in detecting cellular stress signals (e.g., stress-induced ligands or glycolipids [85,88] and glycans [89,90]). The activation of Vδ1 + cells by TCR engagement combined with cy-tokine stimulation (i.e., IL-2 or IL-15) upregulates NKRs, correlating with CD56 expression and potent anti-tumour cytotoxicity [76,91]. ...
March 1994
The Journal of Immunology
... 16 Vγ6 cells also express a semi-invariant TCR, 17,18 and these cells localize primarily to reproductive organs, tongue, and lung. [19][20][21] In adult mice, Vγ5 and Vγ6 cells (and some IL-17-producing Vγ4 cells in the colon) no longer require the thymus for development. They exist mostly as self-generating, tissue-resident cells. ...
December 1993
The Journal of Immunology
... These include the interactions between Neutrophils and Gamma Delta T cell [33], and between B Cell and CD4+ T Cell [34,35] which are both supported by previous studies. CINS was again able to identify key ligands involved in these interactions, TNF, identified as the top ligand in the interaction between neutrophils and Gamma Delta T cells was previously identified as expressed in neutrophils [36] and as a regulator of immune cells Gamma Delta T cells [37], and TNFSF18 identified in interactions between CD4+ T cells and Vascular Endothelial Cells, was also previously reported to mediate the interactions between immune cells and endothelial cells [38]. ...
July 1998
The Journal of Immunology