Human gamma delta T-cells in the epithelium of the gut and in the inflamed synovial tissue preferentially express the V gamma 8 T-cell receptor chain.
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Arthritis, Rheumatoid↗
Biomedical subjects
D L Orsini
Publications and source records attributed to D L Orsini.
Identification of two distinct function gamma delta TCR complexes on the surface of a human T cell clone.
In this study we describe the expression of two T cell receptor (TCR) gamma chains on the surface of a human T cell clone isolated from the peripheral blood. Each gamma chain was part of an independent and functional TCR. The dual receptor T cell clone (and all subclones derived from this clone) had stable expression of this phenotype. Immunoprecipitation studies revealed the expression of non-disulfide linked TCRs by this V gamma 4+V gamma 9+V delta 1+ T cell clone, which was in agreement with the finding that both V gamma gene transcripts were rearranged to C gamma 2-associated joining elements. Both gamma chains were derived from productive rearrangements of different (allelic) genes coding for a V gamma 4+ and a V gamma 9+ gamma-chain, and both were coupled to a V delta 1+ delta chain. Incubation of this V gamma 4+V gamma 9+V delta 1+ T cell clone with TCR gamma-chain-specific MoAbs rapidly induced an increase in intracellular Ca++, indicating that both gamma-chains are functional. Furthermore, this clone responded to stimulation with S. aureus derived superantigens. We suggest therefore that exogenous (super)antigens can trigger dual receptor T cells resulting in activation of these T cells.
Amino Acid Sequence↗
T-cell receptor usage of interleukin-2-responsive peripheral gamma delta T cells.
The majority of human peripheral gamma delta T cells express the V gamma 9 gene in combination with the V delta 2 gene. The diversity of this subset of gamma delta T cells is limited by a preferential usage of the J gamma P gene segment and a highly distinctive junctional motif of the T-cell receptor (TCR) delta chain. We and others have observed that peripheral blood derived V gamma 9+V delta 2+ gamma delta T cells of healthy individuals are activated after stimulation with interleukin-2 (IL-2) in vitro, but only a small percentage of gamma delta T cells subsequently proliferates. To assess whether the proliferating, IL-2-responsive gamma delta T cells represent a selective group of T cells, we have analysed TCR junctional features of IL-2-responsive gamma delta T cells. Out of 30 individuals studied, nine were identified as IL-2-responders and three as IL-2-hyperresponders. The TCR V(D)J gene usage from IL-2 stimulated peripheral blood lymphocytes of these IL-2-(hyper)responsive individuals was analysed. The results showed that in most individuals gamma delta T cells polyclonally expanded after stimulation with IL-2. In two IL-2-hyperresponder individuals, however, a monoclonal expansion of a particular V gamma 9+V delta 2+ gamma delta T cell was found. In one of these individuals, this V gamma 9+V delta 2+ T-cell clone expressed a very rare gamma delta TCR type because of the presence of an Ala within the junctional region at a conserved position relative to V delta framework residues (delta 97), which is very infrequently used by peripheral blood V gamma 9+V delta 2+ cells. This particular clonotype could also be detected in unstimulated PBL samples taken from that individual, and made up for 30% of the total peripheral gamma delta T-cell pool. These data indicate that in general IL-2-responsive V gamma 9+V delta 2+ gamma delta T cells represent a polyclonal population, reflecting in vivo stimulation with multiple antigens or superantigens. In contrast, monoclonal expansions of gamma delta T cells after stimulation with IL-2 can also occur, which may be related to an in vivo stimulation by one particular antigen, rendering this gamma delta T-cell type dominant in the peripheral blood.
Base Sequence↗
High expression of V gamma 8 is a shared feature of human gamma delta T cells in the epithelium of the gut and in the inflamed synovial tissue.
We have analyzed the V-gene usage in gamma delta T cells of the human gut and joint by using a new mAb (B18) specific for V gamma 8 of human TCR-gamma delta+ T cells. The B18+ population constituted a minor subset of the gamma delta T cells in peripheral blood (PB) of healthy persons (6 +/- 5%) and only 1 of 35 gamma delta T cell clones analyzed was positive. In contrast, the B18+ subset was a dominant gamma delta T cell population among intraepithelial lymphocytes (IEL) derived from the human intestine (74 +/- 29, p < 0.002), and two of three IEL clones from patients with coeliac disease were B18+. Interestingly, a higher proportion of B18+ gamma delta T cells was found in the synovial fluid of patients with rheumatoid arthritis (RA) (21 +/- 18%, 0.02 < p < 0.05) compared with normal PB. Furthermore, the B18+ subset was more frequent among IL-2-expanded gamma delta T cells (42 +/- 20%) derived from synovial tissue than among IL-2-expanded cells derived from synovial fluid (p < 0.002) and PB from RA patients (p < 0.02) as well as normal PB (p < 0.002). The V-gene usage of 13 gamma delta T cell clones from the synovial fluid of arthritic patients was analyzed. All B18+ clones (n = 7) expressed mRNA for V gamma 8 together with mRNA for V delta 1 (n = 5) or mRNA for V delta 3 (n = 2). None of the B18- clones expressed V gamma 8 (n = 6). We conclude that the gamma delta T cell that expresses V gamma 8, together with mainly V delta 1, is a major gamma delta T cell subset among the IEL of the gut and a highly frequent subset in the synovial tissue of patients with RA. This subset may correspond to the mouse V gamma 7+ IEL, which has a high degree of amino acid sequence homology with the human V gamma 8 protein.
Adult↗
Functional and molecular characterization of B cell-responsive V delta 1+ gamma delta T cells.
Cells expressing the V delta 1+ gene segment are a minor gamma delta T cell population in human peripheral blood but predominate in epithelial and (inflamed) tissues. The characteristic dendritic-like morphology of these gamma delta T cells is consistent with their putative immune surveillance role in epithelia. Their function, however, remains unknown. We and others previously reported that a subset of V delta 1+ gamma delta T cells proliferates after stimulation with Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines (LCL), but not with fresh peripheral blood-derived B cells. These responses were independent of the type of T cell receptor (TcR) gamma chain co-expressed with the V delta 1 chain. The in vivo relevance of this LCL-mediated activation as well as the nature of the stimulatory ligand on the LCL is not well established. In this study, we tested the proliferative response of V delta 1+ LCL-responsive T cells against non-EBV-transformed B cells, activated through CD40 by murine EL4 B5 cells, and to a panel of B cell lines differing in the expression of EBV nuclear antigen proteins and adhesion/co-stimulatory molecules. The role of the Epstein-Barr virus-derived antigen in the induction of this response could be excluded as the activated (non-EBV-transformed) peripheral blood B cells were also able to induce a proliferative response in the LCL-responsive V delta 1+ T cells. Therefore, the stimulatory ligand on B cells is of cellular rather than of viral origin, and its expression is up-regulated upon activation of B cells. The expression of B7 and CD39 molecules on the surface of activated B cells appeared to be crucial since antibodies to these structures could block the induction of proliferation of the V delta 1+ T cells. Finally, we investigated the diversity of the responding V delta 1+ gamma delta T cell clones by sequence analysis of the TcR delta junctional regions. No restricted V-D-J sequences were found among the LCL-responsive V delta 1+ T cell clones, arguing strongly against a mono- or oligoclonal V delta 1+ gamma delta T cell response to LCL. These findings may explain the presence of polyclonally activated V delta 1+ T cells in inflamed tissues where activated B cells are often present.
Adenosine Triphosphatases↗
A subset of V delta 1+ T cells proliferates in response to Epstein-Barr virus-transformed B cell lines in vitro.
It has previously been shown that murine tissue derived T-cells expressing the gamma delta T-cell receptor can respond to autologous (stressed) cells implying the recognition of an autoantigen. Here we report that a large proportion of human synovial tissue and peripheral blood derived V delta 1+ gamma delta T-cell clones proliferate in response to stimulation with autologous and allogeneic EBV-transformed B-lymphoblastoid cell lines (LCL). In contrast, V delta 1- gamma/delta and alpha/beta TCR+ T-cell clones isolated from the same tissue samples did not display proliferation towards the LCL. The proliferative response of these V delta 1+ clones was dependent on contact between responder and stimulator cells and could be blocked by a MoAb to LFA-1 and by antibodies to the gamma delta TCR/CD3 complex. Because the responses of these clones to LCL cells appear to be independent of the gamma-chain co-expressed with the V delta 1-chain these resemble a superantigen response. The capacity of this subset of V delta 1+ T-cell clones to proliferate after stimulation with LCL may imply the recognition of an endogenous epitope. Moreover, since so far we have been able to isolate only LCL reactive gamma delta T-cell clones from synovial tissue and peripheral blood of reactive arthritis patients and not from peripheral blood of healthy individuals, the frequency of such 'autoreactive' gamma delta cells may be higher in these patients.
Antibodies, Monoclonal↗
Diversity in antigen recognition by Mycobacterium tuberculosis-reactive T cell clones from the synovial fluid of rheumatoid arthritis patients.
In a previous study we have shown that synovial fluid mononuclear cells from many rheumatoid arthritis (RA) patients exhibit an enhanced response to M. tuberculosis antigens as compared to peripheral blood mononuclear cells. The 65-kDa heat-shock protein of M. tuberculosis was shown not to play an important role in this response, therefore other mycobacterial proteins must be involved. In this study we have investigated the possibility that synovial fluid T cells from RA patients predominantly recognize a limited number of M. tuberculosis antigens, as a result of a lesion-specific activation of only those M. tuberculosis-reactive T cells that have cross-reacted with joint-related autoantigens. From the synovial fluid of four RA patients M. tuberculosis-reactive T cell clones were isolated and analyzed for their phenotype, HLA-DR restriction and proliferation to immunoblot fractions containing sodium dodecyl sulfate-polyacrylamide gel-separated M. tuberculosis proteins of known molecular weight range. The overall M. tuberculosis immunoblot recognition pattern of the clones was strikingly heterogeneous. Within a panel of 15 clones 12 different antigenic specificities could be distinguished. In other words, we did not observe a dominant recognition of a few M. tuberculosis antigens by synovial fluid T cells. This argues against the hypothesis that the elevated synovial T cell reactivity against M. tuberculosis is a reflection of an in vivo expansion of a limited number of different types of M. tuberculosis-reactive T cells as a result of a cross-reaction with putative joint autoantigens.
Antigens, Bacterial↗
Some correlates of intra- and interhemispheric speech organization after left focal brain injury.
Determinants of inter- and intrahemispheric organization following left focal injury were examined with data deriving from four different studies that used three different assessment methods (amobarbital, temporal lobectomy, dichotic listening). With regard to interhemispheric reorganization, the results revealed that the earlier the lesion onset, the higher the probability of a biomodal hemispheric reorganization (speech and hand). A unimodal reorganization (speech only) was tied to a later occurring lesion, but one before age six. Furthermore, interhemispheric speech reorganization was associated with an early lesion onset while intrahemispheric speech maintenance was linked to a later lesion onset. The results are discussed in terms of hemispheric plasticity and functional maturity.
Brain↗
Null hypothesis disrespect in neuropsychology: dangers of alpha and beta errors.
To understand why there are so many inconsistencies and contradictory findings among hemispheric-asymmetry studies, data were analyzed from a large study of 300 left-handers. These data included information on familial sinistrality (FS), handwriting posture (HPO), a measure of cognitive performance, and five measures of hemispheric specialization. Using computer simulation methodology, 40 independent samples of 36 to 65 subjects each were drawn randomly with replacement. The sample data were analyzed and the results compared to those of the parent "population." Often, the samples poorly reflected the parent "population," and some procedures substantially inflated error rates. These procedures are discussed and specific guidelines suggested. These results are also discussed in the broader context of the necessity for investigators in neuropsychology to differentiate between the statistical and clinical significance of research findings; and to develop a more positive attitude toward the design, execution, and publication of replication studies.
Adult↗
Individual differences in the cerebral organization of language using input and output interference measures of lateralization.
The literature on the relationship between cerebral lateralisation and the combined effects of sex and handedness, reveals many discrepant findings. In an effort to clarify these discrepancies, three different types of interference cerebral lateralization tasks were used in a relatively large sample of normal individuals. Handedness differences were found in the expected direction on all three lateralization measures: input interference (dichotic listening), and two output interference measures, a motor-motor interference task (concurrent finger tapping and verbal fluency) and a motor-cognitive interference task (concurrent finger tapping and silent reading). A sex difference, however, was found on only the motor-motor interference task. These results suggest that possible sex differences in cerebral lateralisation may be less prominent among particular types of interference laterality tasks, and more reliably found with motor-motor interference lateralization measures.
Journal Article↗
Handedness distribution in a residential population with severe or profound mental retardation.
Handedness within a sample of mentally retarded subjects was assessed using a procedure that includes a large number of items appropriate for lower functioning subjects, with multiple presentations within and between sessions one week apart. Results revealed a dramatic shift from the normal right-handed bias primarily due to the presence of a large mixed-handedness subtype, which proved to be ambiguously handed in that these subjects showed inconsistent hand preference within items. Reasons why this subtype has not been reported previously were discussed, and a model was postulated to explain the resultant handedness distribution in terms of probable central nervous system substrate.
Adult↗
A syndrome of pathological left-handedness. Correlates of early left hemisphere injury.
A pattern of correlative changes in lateralization in individuals with known or suspected brain injury recently has been advanced as the syndrome of pathological left-handedness (PLH). This syndrome, which is believed to be caused by an early left-sided cerebral lesion, may include asymmetric motor and/or trophic changes on the right side of a body part in addition to changes in higher-level cognitive processing abilities. Several clinical case studies have provided support for such a syndrome. Despite their clinical subject to inherent biases of selection. The present study was therefore designed to evaluate the PLH syndrome in a systematic fashion by using a large number of brain-injured and normal subjects. The incidence of each of the putative elements of the PLH syndrome was investigated. The results suggest that traits such as atypical cerebral speech representation, motor impairment of the nondominant hand, and hypoplasia of the right foot are salient features of the syndrome. The results are discussed with reference to clinical diagnostic implications.
Adolescent↗
Handedness patterns in autism suggest subtypes.
The present study reports preliminary data from two unselected samples of carefully diagnosed autistic subjects (children and adults) and an assessment procedure that includes a large sample of items, appropriate for lower-functioning autistic subjects, with multiple presentations within and between sessions 1 week apart. The study seeks to determine (1) whether a raised incidence of non-right-handedness exists in these samples (2) if so, what constructs best represent this shift in the handedness distribution (i.e., phenotype and CNS substrate) and (3) whether these handedness phenotypes are associated with different levels of cognitive functioning. The results reveal a dramatic shift away from right-handedness in both autistic samples, due to a raised incidence of two phenotypes, manifest left-handedness and ambiguous handedness. The ambiguously handed, who were postulated to represent substantial bilateral CNS pathology due to early brain injury, were found to have much lower intellectual scores in one of the study samples.
Adolescent↗
The role of familial sinistrality in cerebral organization.
The literature on the relationship between familial sinistrality (FS) and laterality is conflicting. A large scale investigation employing multiple measures of laterality assessment and rigorous methods of handedness and FS determination was conducted with a normal population of left- and right-handers. The results failed to find a relationship between FS and hemispheric representation of speech despite the fact that a robust relationship was found between handedness and hemispheric speech specialization. Possible reasons for these null findings are discussed.
Adolescent↗
The pathological left-handedness syndrome.
A clinical syndrome of pathological left-handedness (PLH) is proposed to identify the pattern of correlative changes in lateral development associated with early brain injury in some manifest left-handers. This syndrome is believed to be caused by a hemispheric lesion that is predominantly left-sided (or bilateral asymmetric), which onsets before Age 6, and which encroaches upon the critical speech zones of the frontotemporal/frontoparietal cortex. The pattern of changes may include any or all of the following features: shifts in manual dominance, trophic changes in the extremities, transfer of hemispheric speech, and/or intrahemispheric reorganization of visuospatial cognitive functions. Although some of these correlates of PLH have long been known, they have not been recognized as an interrelated pattern of traits that constitute a clinical syndrome. Identification of these individuals, all manifest left-handers, will be shown to have implications for diagnosis/remediation and for models of recovery of function.
Adolescent↗
Pedal asymmetries and handedness.
The relationship between pedal asymmetries and handedness has been the subject of several investigations. Support for pedal asymmetries occurring in the normal population have been reported which are claimed to be a function of handedness and sex. If true, these asymmetries would confound the assessment of trophic changes due to localized brain injury. However, at least four attempts to replicate these results have failed. The present study was undertaken to reassess this hypothesis using more rigorous measurement of handedness and foot length with a more representative sample allowing for larger hand by sex groups than has been previously used. No differences in the direction of foot size were found regardless of hand or sex classification.
Adolescent↗