Restricted Usage of T Cell Receptor Vα/Jα Gene Segments with Different Nucleotide but Identical Amino Acid Sequences in HLA-DR3+ Sarcoidosis Patients

Grünewald, Johan; Hultman, Thomas; Bucht, Anders; Eklúnd, Anders; Wigzell, Hans

doi:10.1007/bf03401553

Cited by 57 publications

(45 citation statements)

References 36 publications

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“…In early attempts, PCR techniques were applied to address this question, but without any distinct findings [14]. Using new techniques, we initially found a higher-than-normal usage of Vβ22 in lung-accumulated T-cells from HLA-DRB1*03 + patients [16], and in the present report further establish that a substantial part of lung-accumulated Vα2.3 + T-cells also express Vβ22 in HLA-DRB1*03 + patients.…”

Section: Discussionmentioning

confidence: 48%

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T-cell receptor–HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis

et al. 2015

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In pulmonary sarcoidosis, CD4+ T-cells expressing T-cell receptor Vα2.3 accumulate in the lungs of HLA-DRB1*03 + patients. To investigate T-cell receptor-HLA-DRB1*03 interactions underlying recognition of hitherto unknown antigens, we performed detailed analyses of T-cell receptor expression on bronchoalveolar lavage fluid CD4 + T-cells from sarcoidosis patients. Pulmonary sarcoidosis patients (n=43) underwent bronchoscopy with bronchoalveolar lavage. T-cell receptor α and β chains of CD4 + T-cells were analysed by flow cytometry, DNA-sequenced, and threedimensional molecular models of T-cell receptor-HLA-DRB1*03 complexes generated.Simultaneous expression of Vα2.3 with the Vβ22 chain was identified in the lungs of all HLA-DRB1*03 + patients. Accumulated Vα2.3/Vβ22-expressing T-cells were highly clonal, with identical or near-identical Vα2.3 chain sequences and inter-patient similarities in Vβ22 chain amino acid distribution. Molecular modelling revealed specific T-cell receptor-HLA-DRB1*03-peptide interactions, with a previously identified, sarcoidosis-associated vimentin peptide, (Vim)429-443 DSLPLVDTHSKRTLL, matching both the HLA peptide-binding cleft and distinct T-cell receptor features perfectly.We demonstrate, for the first time, the accumulation of large clonal populations of specific Vα2.3/Vβ22 T-cell receptor-expressing CD4 + T-cells in the lungs of HLA-DRB1*03 + sarcoidosis patients. Several distinct contact points between Vα2.3/Vβ22 receptors and HLA-DRB1*03 molecules suggest presentation of prototypic vimentin-derived peptides. @ERSpublications Clonal CD4 + lung T-cells associating with HLA-DRB1*03 molecules indicate specific antigens in pulmonary sarcoidosis

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Section: Discussionmentioning

confidence: 48%

“…Earlier analyses of the TCR α chain of bronchoalveolar lavage (BAL) Vα2.3 + CD4 + T-cells indicated selection towards specific antigens [14]. Interestingly, HLA-DRB1*0301 and HLA-DRB3*0101 molecules are structurally and functionally similar and seem to present a highly similar peptide antigen repertoire, including identical epitopes [15].…”

Section: Cd4mentioning

confidence: 99%

T-cell receptor–HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis

et al. 2015

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“…It is essential to remember that the AV2S3+ cell population is not a T-cell clone. The variable a-chain can associate with different variable b-chains [31]. MALLONE et al [32] showed that different T-cell clones can exhibit different avidity towards the same antigen, with the outcome that some clones only proliferate, whereas others both proliferate and produce cytokines in response to a given antigen concentration.…”

Section: Discussionmentioning

confidence: 99%

Antigen-specific multifunctional T-cells in sarcoidosis patients with Löfgren’s syndrome

Wikén¹,

Ostadkarampour²,

Eklúnd³

et al. 2011

Eur Respir J

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Sarcoidosis is a granulomatous disease of unknown aetiology, mainly affecting the lungs. Recently, T-cell responses towards a specific mycobacterial protein, catalase-peroxidase (mKatG), were observed in sarcoidosis patients.Bronchoalveolar lavage (BAL) fluid and peripheral blood were obtained from a total of 23 sarcoidosis patients, of whom 13 had Löfgren's syndrome and lung accumulations of T-cell receptor AV2S3+ T-cells. Using six-colour flow cytometry in combination with intracellular cytokine staining, T-cell subsets were studied with regard to interferon (IFN)-c, tumour necrosis factor (TNF) and interleukin-2 production, after stimulation with mKatG or Mycobacterium tuberculosis purified protein derivate (PPD).Stimulation with mKatG resulted in higher simultaneous IFN-c and TNF production, but less single IFN-c production, from total BAL fluid CD4+ T-cells of Löfgren's syndrome patients, when compared with non-Löfgren's patients. In contrast, PPD stimulation gave rise to largely similar cytokine responses in both patient subgroups. Furthermore, mKatG stimulated higher IFN-c production in BAL fluid and blood AV2S3+ T-cells than AV2S3-T-cells, whereas the opposite was seen in BAL fluid with PPD stimulation.Our finding that patients with Löfgren's syndrome exhibited a more pronounced multifunctional cytokine profile (simultaneous IFN-c and TNF production) towards the mycobacterial protein mKatG may help to explain the distinct disease presentation in this patient subgroup.

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“…The involvement of public TCRs in malignancy was also observed in tumorassociated antigen-specific T cells from melanoma [11][12][13][14][15], synovial sarcoma and prostate cancer [16][17] (Table 1). Public TCRs also occurred in autoimmune diseases such as multiple sclerosis [18], reactive arthritis [9], aplastic anemia [20], psoriasis vulgaris [21], systemic sclerosis [22], sarcoidosis [23], and rheumatoid arthritis [24] (Table 1). In addition, examples of public TCRs were extensively observed in non-human primates and mice [25].…”

Section: Introductionmentioning

confidence: 99%

Determinants of public T cell responses

et al. 2012

Cell Res

118

112

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Historically, sharing T cell receptors (TCRs) between individuals has been speculated to be impossible, considering the dramatic discrepancy between the potential enormity of the TCR repertoire and the limited number of T cells generated in each individual. However, public T cell response, in which multiple individuals share identical TCRs in responding to a same antigenic epitope, has been extensively observed in a variety of immune responses across many species. Public T cell responses enable individuals within a population to generate similar antigen-specific TCRs against certain ubiquitous pathogens, leading to favorable biological outcomes. However, the relatively concentrated feature of TCR repertoire may limit T cell response in a population to some other pathogens. It could be a great benefit for human health if public T cell responses can be manipulated. Therefore, the mechanistic insight of public TCR generation is important to know. Recently, high-throughput DNA sequencing has revolutionized the study of immune receptor repertoires, which allows a much better understanding of the factors that determine the overlap of TCR repertoire among individuals. Here, we summarize the current knowledge on public T-cell response and discuss future challenges in this field.

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Restricted Usage of T Cell Receptor Vα/Jα Gene Segments with Different Nucleotide but Identical Amino Acid Sequences in HLA-DR3+ Sarcoidosis Patients

Cited by 57 publications

References 36 publications

T-cell receptor–HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis

T-cell receptor–HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis

Antigen-specific multifunctional T-cells in sarcoidosis patients with Löfgren’s syndrome

Determinants of public T cell responses

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