Abstract: Oral tolerance was first detailed almost 100 years ago, and since then, it has been shown repeatedly that feeding a wide variety of nonpathogenic antigens can inhibit subsequent systemic immune responses. All systemic immune responses are susceptible, but the degree and scope of the suppression depends on the nature and dose of the fed antigen. Oral tolerance has been described in most mammals, including humans, and it may be the homeostatic mechanism that prevents hypersensitivity to food antigens, as is found in celiac disease. A similar process may prevent the aberrant immune responses to commensal bacteria that occur in inflammatory bowel disease. The ability of oral tolerance to modulate experimental models of autoimmune and inflammatory disease has led to clinical trials in such diseases as rheumatoid arthritis, multiple sclerosis, and type I diabetes, with only variable success. Despite intense research, the exact mechanisms responsible for the systemic tolerance and the reasons why tolerance is the default response to many fed antigens remain controversial. Early studies suggested that CD8+“suppressor” T cells were important, but it is now accepted that it may involve either anergy/deletion of CD4+ T cells, or the induction of regulatory CD4+ T cells that produce IL‐10 and/or TGFβ. There may also be a role for CD4+ CD25+ Treg, but how and when all these different mechanisms operate is still unclear. The ability of fed antigens to induce tolerance probably reflects their uptake by “quiescent” antigen‐presenting cells in the intestine, with presentation to specific CD4+ T cells in the absence of costimulation, or with the involvement of inhibitory costimulatory molecules. Dendritic cells in the Peyer's patches or mucosal lamina propria are the most likely APCs involved, but it remains to be determined exactly where these interactions occur and what the precise nature of the relevant dendritic cells is.

SummaryImmune stimulating complexes (ISCOMS) containing the saponin adjuvant Quil A are vaccine adjuvants that induce a wide range of immune responses in vivo, including strong class I major histocompatibility complex (MHC) ‐restricted cytotoxic T‐lymphocyte activity. However, the antigen‐presenting cell responsible for the induction of these responses has not been characterized. Here we have investigated the role of dendritic cells (DC) in the priming of antigen‐specific CD8+ T cells in vitro by ISCOMS containing ovalbumin. Resting bone marrow DC pulsed with ovalbumin ISCOMS efficiently prime resting CD8+ T cells through a mechanism that is transporter associated with antigen processing (TAP) dependent, but independent of CD40 ligation and CD4+ T‐cell help. Lipopolysaccharide‐induced maturation of DC markedly enhances their ability to prime CD8+ T cells through a mechanism which is also independent of CD4+ T‐cell help, but is dependent on CD40 ligation. Furthermore, DC maturation revealed a TAP‐independent mechanism of CD8+ T‐cell priming. Our results also show that class I MHC‐restricted presentation of ovalbumin in ISCOMS by DC is sensitive to chloroquine and brefeldin A but insensitive to lactacystin. We suggest that DC may be the principal antigen‐presenting cells responsible for the priming of CD8+ T cells by ISCOMS in vivo and that targeting these vectors to activated DC may enhance their presentation via a novel pathway of class I antigen processing.

T cell-mediated immunity is important in the control of chlamydia infection but chlamydia-specific T cells are also implicated in the inflammation and tissue damage which characterize chlamydia associated diseases. To investigate target antigens of the T cell-mediated immune response to chlamydia infection, Chlamydia trachomatis-specific CD4+ T cell clones were isolated from a patient with chlamydia-induced reactive arthritis. T cell immunoblotting indicated that an antigen of approximately 60 kilodaltons molecular mass was recognized, and recombinant 60 kilodalton cysteine-rich outer membrane 2 (OMP2) proved to be stimulatory. By using deletion constructs and synthetic peptides an epitope presented by HLA-DRB1*0401 was defined and proved to contain the nonamer peptide within the OMP2 sequence predicted to have the greatest binding affinity for DRB1*0401 The sequence of the epitope is conserved in all C. trachomatis strains but not in C. pneumoniae. Investigation of patients with acute urethritis and additional patients with sexually acquired reactive arthritis showed that OMP2-reactive T cells were readily detectable in peripheral blood and synovial fluid. Thus OMP2 is a target antigen of the T cell-mediated immune response to CT infection.

OBJECTIVE:Reactive arthritis (ReA), a HLA-B27 associated arthropathy, develops in susceptible people after infection with certain bacteria. T cells have been implicated in the pathogenesis of the arthritis but which of the different subsets is involved is still debated. This study has further elucidated the role of the CD4+ and CD8+ T cells by examining the expression of various surface markers associated with activation. METHODS:Three colour flow cytometry was used to examine the phenotype of the T cells within the synovial fluid (SF) and peripheral blood (PB) of ReA patients. RESULTS:ReA SF, compared with paired PB, contained a higher percentage of CD69+, CD25+, and HLA-DR+ CD3+ T cells. The majority of SF T cells also expressed the putative memory marker CD45RO. Within the T cell subsets, CD25 was expressed primarily on the CD4+ T cells; however more CD8+ T cells were HLA-DR+. CONCLUSION:The results show that both CD4+ and CD8+ T cell populations demonstrate evidence of recent activation. Whether these cells are involved in inducing inflammation, regulating the inflammation, or have become active as a result of migration through the endothelium, remains to be determined by functional studies.

We have studied the human gamma delta T-cell response to Yersinia enterocolitica, a facultative intracellular bacterium which causes gastroenteritis and, particularly in human leucocyte antigen (HLA)-B27+ individuals, reactive arthritis (ReA). A marked proliferation of that cytotoxic gamma delta T cells is seen when Yersinia-infected lymphoblastoid cell lines or fixed intact Yersinia are added to cultures of mononuclear cells derived from the synovial fluid of ReA patients or from the peripheral blood of healthy donors. In contrast, heat-inactivated Yersinia fail to stimulate the gamma delta T-cell response. The gamma delta T-cell lines generated killed both autologous and allogeneic infected cell lines. Interestingly, a T-cell line generated from synovial fluid mononuclear cells (SFMC) killed infected autologous cell lines and a cell line matched for HLA-B27 less well than infected allogeneic target cells. gamma delta T-cell clones isolated from this line were found to express V gamma 9V delta 2 T-cell receptor (TCR) and also killed infected mismatched cells more efficiently than autologous targets. Moreover, from experiments using major histocompatability complex (MHC)-deficient cell lines, it was apparent that target cell recognition was MHC independent. Our results suggest that gamma delta T cells can be involved in immunity to Yersinia enterocolitica and should be taken into account when considering immunopathological mechanisms leading to reactive arthritis.