While studying the alpha beta T cell receptor repertoire in rheumatoid arthritis (RA) patients, we found that the frequency of V beta 14+ T cells was significantly higher in the synovial fluid of affected joints than in the peripheral blood. In fact, V beta 14+ T cells were virtually undetectable in the peripheral blood of a majority of these RA patients. beta-chain sequences indicated that one or a few clones dominated the V beta 14+ population in the synovial fluid of individual RA patients, whereas oligoclonality was less marked for other V beta's and for V beta 14 in other types of inflammatory arthritis. These results implicate V beta 14-bearing T cells in the pathology of RA. They also suggest that the etiology of RA may involve initial activation of V beta 14+ T cells by a V beta 14-specific superantigen with subsequent recruitment of a few activated autoreactive v beta 14+ T cell clones to the joints while the majority of other V beta 14+ T cells disappear.
Infection with Staphylococcus aureus and the production of toxic shock syndrome toxin-1 (TSST-1) have been implicated in the pathogenesis of toxic shock syndrome. Previous in vitro studies have demonstrated that TSST-1 is a powerful but selective stimulator of human T cells, and that the majority of activated cells express the TCR V beta 2 gene segment. We therefore studied patients with toxic shock syndrome using a modification of the PCR to determine if expansion of V beta 2+ T cells is a marker of the in vivo disease process. Five of eight patients studied demonstrated markedly elevated levels of circulating V beta 2+ T cells, whereas none showed significantly elevated levels of T cells expressing other V beta gene segments. The results suggest that toxin-mediated T cell activation, which involves a large fraction of the human T cell repertoire, may be critical in the pathogenesis of this disease.
Multiple sclerosis is an autoimmune disease in which T lymphocytes reactive to myelin basic protein (BP) could play a central role. T cells specific for BP were cloned from the blood of multiple sclerosis patients and normal individuals, and expression of T-cel receptor variable region genes was analyzed. A remarkable bias for use of f-chain variable region (VP) 5.2 and, to a lesser extent, Vj36.1 was seen among BP-specific clones from patients but not from controls. Multiple sclerosis (MS) is an immune-mediated disease characterized by central nervous system mononuclear cell infiltration and demyelination. Although the pathogenesis of MS is unknown, both genetic and environmental factors have been implicated in the disease process. Major elements ofthe genetic predisposition include an association of disease with particular class II major histocompatibility complex (MHC) haplotypes, in particular HLA-DR2 and -DQwl (1-5), as well as with certain polymorphisms within the T-cell receptor (TCR) a-chain and (3-chain gene complexes (6-9). These studies suggest that the disease involves CD4+ T cells bearing af3 TCR. In support of this idea, CD4+ T cells represent a major component of mononuclear cells in the brains of active patients (10), and limited sets of a-chain TCRs are present within central nervous system tissue of MS patients but not controls (11).T lymphocytes that recognize myelin basic protein (BP) have been shown to have potent demyelinating and encephalitogenic activity in animals (12-18). Accumulating evidence also suggests that BP-specific T cells may contribute to the pathogenesis ofMS. Thus, cells selected from MS patients on the basis of in vivo activation have specificity for BP (19). In addition, the frequencies of BP-reactive T cells are increased Monoclonal antibodies directed to these regions or synthetic peptides with sequences common to these TCR V regions can both protect and treat animals with clinical signs of experimental autoimmune encephalomyelitis (21,22,(25)(26)(27). For a similar approach to be applied to MS patients, it is critical to know if potentially pathogenic T cells also preferentially use a limited set of V region genes. In this manuscript, we analyze the TCR Va and Vf3 genes expressed in BP-specific T cells selected from the blood of MS patients and normal individuals. MATERIALS AND METHODSPatients. Blood samples were obtained from seven patients being followed at the Oregon Health Sciences University MS clinic. All patients had clinically and laboratory-supported definite MS with an average ambulation index of 3.2 + 1.7 (range 2-6) and an average Kurtzke disability status score of 3.8 + 2.0 (range 2-6). Four patients had relapsing/remitting disease, and three patients had chronic progressive disease. The normal individuals were from the Veterans Affairs Medical Center, selected on the basis of a positive proliferative response of peripheral blood mononuclear cells (PBMC) to human BP in culture (20). All subjects were HLA-typed by standard serological methods at the...
Mouse T-cell hybridomas bearing human Vp elements were produced by transfection of human/mouse hybrid T-cell receptor 18-chain genes into a mouse T-cell hybridoma lacking an endogenous #-chain gene. These hybridomas were entirely mouse in origin except for the human Vp region. These cells were used to immunize mice against human V13 elements. Mouse monoclonal antibodies have thus been generated against human Vp13.1 and -13.2. We expect that the method outlined in this paper will be useful in the production of monoclonal antibodies specific for other human V13 or V.elements.The receptor for antigen on most peripheral T cells is made of a and 13 chains. Usually these T-cell receptors (TCRs) engage antigen in the form of peptides, derived from the antigen, bound to cell surface major histocompatibility complex (MHC) molecules (1-4). The specificity of the TCR for this complex ligand is determined by the five variable elements (Va, Ja, V13, Do, and JO3) of the a and 13 chains as well as non-germ-line-encoded junctional regions (5-8). Exceptions to this rule have been documented by us and others. These are proteins that stimulate T cells bearing the appropriate V13 element almost independently ofcontributions from other parts of the TCRs borne by the T cells (9-22). Such proteins, called superantigens because they stimulate large numbers ofT cells, are encoded by microorganisms including retroviruses, bacteria, and mycoplasma (22-29).There is considerable interest in the control and consequences of the T-cell repertoire in humans and other species. Obviously a detailed understanding of the T-cell repertoire would require knowledge of all the V,, Ja, V13, D13, and Jo combinations present in a given individual. Such knowledge will not be available in the foreseeable future. However, much has already been learned from studies of the distribution between animals of just one of the TCR variable elements, V13. Examination of V13 expression in mice has been used to study positive selection, T-cell tolerance, autoimmunity, and the consequences of attack by superantigens (22).Similarly, V13 expression in humans has been used to study the effects of superantigens and also to examine the repertoires of T cells involved in inflammatory and autoimmune disease (18,19,29,30 MATERIALS AND METHODSPreparation of RNA and cDNA and Amplification by QPCR. Total RNA was prepared from phytohemagglutinin-, antihV,013
Streptococcal exotoxins have been implicated in the pathogenesis of a toxic shock-like syndrome and scarlet fever. Previous studies have demonstrated that these toxins are potent stimulators of human T cells and have structural homology to staphylococcal enterotoxins. In the current study, we investigated the mechanism by which streptococcal erythrogenic toxins type A (SPEA) and B (SPEB) activate T cells and compared it with anti-CD3 and the known "superantigen" staphylococcal enterotoxin B. SPEA was found to selectively activate T cells bearing V beta 8, V beta 12, and V beta 14, whereas SPEB selectively activated T cells bearing V beta 2 and V beta 8. Furthermore, fibroblasts transfected with MHC class II molecules were capable of presenting SPEA and SPEB to purified T cells. The T cell response to these toxins, however, was not MHC-restricted. Although the streptococcal exotoxins stimulated both CD4+ and CD8+ T cells, SPEA but not SPEB stimulated the CD4+ T cell subset proportionately more than the CD8+ T cell subset. Our results indicate that SPEA and SPEB, like the staphylococcal enterotoxins, are superantigens and suggest a mechanism by which they may mediate particular systemic syndromes associated with streptococcal infections.
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