Limited heterogeneity of biased T‐cell receptor Vβ gene usage in lung but not blood T cells in active pulmonary sarcoidosis

Abstract

Sarcoidosis is a multisystem disorder characterized by non‐caseating granulomas and the accumulation of CD4+ T cells in involved tissues such as the lung. To evaluate the diversity of the CD4+ T‐cell repertoire in this disorder, a detailed clonal analysis was performed in five individuals with active sarcoidosis who demonstrated preferential accumulation of T cells expressing the T‐cell receptor variable gene family Vβ8 in either the lung or blood. In three individuals, analysis of unselected samples of nucleotide sequences derived from Vβ8+ lung T cells demonstrated degrees of clonality ranging from 11% to 46%, indicating the expansion of limited numbers of Vβ8+ T‐cell clones in the lung. Analysis of the corresponding deduced amino acid sequences demonstrated common VDJ junctional amino acid residues in the dominant Vβ8+ T‐cell clones derived from two oligoclonal Vβ8+ lung T‐cell populations, consistent with an antigen‐specific T‐cell response. In contrast, analysis of Vβ8+ CD4+ T cells from the blood of an individual with a marked bias for peripheral blood Vβ8+ T cells demonstrated no evidence of oligoclonality, suggesting that the stimulus for circulating biased Vβ‐specific T cells in sarcoidosis may derive from a different, perhaps superantigenic, origin. Clinical improvement in the disease either in response to treatment with corticosteroids or as a result of spontaneous resolution was associated with a decrease in the proportion of Vβ8‐specific T cells in the biased lung and/or blood T‐cell compartments. Together, these observations are consistent with a role for this T‐cell subset in the clinical manifestations of active granulomatous disease.

Sarcoidosis: immunopathogenetic concepts and their clinical application

“…These findings are consistent with an antigen-driven T-cell activation and the limited clonality of T-cells could also be demonstrated in sarcoid lung T-cells by analysing the nucleotide sequence of the TCR [156]. The association of this oligoclonality with the course of the disease is demonstrated by the fact that oligoclonality decreases after clinical improvement of the disease either by spontaneous remission or after corticoid therapy [156]. In addition, in some cases an amino acid motif in the V β /J β -region of the TCR could be identified which had not been described before and might therefore be typical for sarcoidosis [151].…”

“…However, KLEIN et al [89] demonstrated an increased percentage of V β 2, V β 3, V β 6 and V β 8 families in intradermal lesions of Kveim skin-tests compared with peripheral blood and that this increase was oligoclonal. These findings are consistent with an antigen-driven T-cell activation and the limited clonality of T-cells could also be demonstrated in sarcoid lung T-cells by analysing the nucleotide sequence of the TCR [156]. The association of this oligoclonality with the course of the disease is demonstrated by the fact that oligoclonality decreases after clinical improvement of the disease either by spontaneous remission or after corticoid therapy [156].…”

“…The rise and fall of oligoclonality of BAL CD4+ cells can be observed in berylliosis [159] and that of CD8+ cells in hypersensitivity pneumonitis [161]. More-over, BAL T-cell oligoclonality vanished in patients with sarcoidosis or hypersensitivity pneumonitis after spontaneous resolution or after treatment of the respective dis-order [156,160]. These observations in interstitial lung diseases of known origin suggest that the skewing of the TCR V β families in sarcoidosis is the result of an oligoclonal T-cell activation by a still elusive "sarcoid agent".…”

Sarcoidosis: Internal medicine perspective

“…A cardinal feature of sarcoidosis is the presence of CD4+ T cells that interact with antigen-presenting cells to initiate the formation and maintenance of granulomas [75]. The oligoclonal αβ T-cell repertoire observed in sarcoidosis suggests that the triggering antigens favor progressive accumulation and activation of selective T-cell clones [76]. These activated CD4+ cells differentiate into type 1 helper T (Th1)-like cells and secrete predominantly interleukin-2 and interferon-γ, augment macrophage TNF-α production, and amplify the local cellular immune response [77].…”

T Cell Receptor Vβ Repertoire in Bronchoalveolar Lavage in Wegener’s Granulomatosis and Sarcoidosis

“…These cells are activated and reduced numbers of cell surface TCR in the presence of increased TCR mRNA levels suggest downregulation of the TCR of pulmonary T cells in response to recent exposure to antigen [6]. Studies on the usage of TCR genes disclosed increased utilization of a restricted pattern of TCR Vα and Vβ gene products in the lung as compared with the blood in the majority of these patients, suggesting that the pulmonary T cell population is composed of an expanded oligoclonal component which superimposes itself on a polyclonal background [7, 8, 9, 10, 11, 12, 13, 14]. These clones are being further characterized to elucidate the nature of the putative antigens involved in the pathogenesis of sarcoidosis.…”