T cell antigen receptor usage, phenotype and cytokine production in human diseases

<p>T lymphocytes are of critical importance for initiating and controlling immune responses, as the T cell receptor (TCR) for antigen allows a highly specific antigen recognition. Determination of TCR usage and characterization of T cell subsets in different diseases helps us understand the underlying immunopathogenic mechanisms, and may also lead to the development of new therapeutic approaches.</p><p>TCR usage was analyzed at the protein level by anti-TCR Va and V[beta] antibodies and flow cytometry. Vp-specific PCR amplification was followed by CDR3 fragment length analysis, cloning and sequencing or determination of J[beta] gene segment usage. Functional aspects were investigated via antibody staining for cell surface markers or intracellular cytokines.</p><p>In allergic alveolitis most patients had lung-restricted CD8+ expansions of T cells using particular V[alpha] or V[beta] segments. These expansions, some of which were dramatic, normalized with clinical improvement. Similarly, patients with allergic asthma developed CD8+ T cell expansions in their lungs after allergen inhalation provocation. The correlation with antigen exposure implicates the expanded I cells in the pathogeneses of these diseases.</p><p>In B-cell malignancies the immunoglobulin idiotype may serve as an autoantigen, being recognized by T cells that may have the capacity to control the myeloma tumour clone. Patients with multiple myeloma had more CD8+ T cell expansions, all of which were highly clonal, compared to age-matched controls. Interestingly, expansions were particularly common in patients with a low tumour burden. In Wegener's granulomatosis, a systemic vasculitis of unknown aetiology, very large T cell expansions were previously demonstrated in the CD4+ subset. We determined a high degree of clonality of all the expansions studied. Of utmost interest was the finding of a common, dominating TCR CDR3-motif that was found in CD4+ V[beta]8+ T cell expansions of several unrelated patients sharing the HLA DRB1*0401 allele, but not in age- and HLA-matched controls. This finding therefore suggests the existence of a specific vasculitis-associated antigen.</p><p>A phenotypic analysis of T cell subsets in lung and blood of pulmonary sarcoidosis patients was undertaken, focusing on activation markers, adhesion molecules, and costimulatory molecules. There was substancial activation of CD4+ as well as of CD8+ lung T cells, and in the lung increased numbers of CD26+ CD28-CD57+ cells, indicating clonally expanded T helper 1 cells. Significantly more cells capable of producing IFN[gamma] and TNF[alpha], and fewer cells producing IL-4, were detected in both CD4+ and CD8+ lung T cell subsets compared to peripheral blood. Thus both subsets may contribute to the inflammatory process in the lung. The tendency to a relatively less pronounced Th1 response in HLA-DR17+ patients may be related to the very good prognosis of this patient group.</p><p>These studies directs the attention to the potentially very important role for CD8+ T cells in several inflammatory pulmonary disorders.</p>