Mucosal T-cell responses to enteric infection.

Although immunologists typically examine immune responses in peripheral lymphoid tissues, mucosal surfaces are the first sites at which most antigens are encountered. The role of lymphocytes in the gut-associated lymphoid tissue (GALT) in the production of secretory IgA has been well characterized. Although T cells of the GALT are located in areas likely to have a key role in cell-mediated immunity at mucosal surfaces, the ways in which these cells help defend against mucosal infection are only beginning to be understood.

Helminth-induced immunoregulation of an allergic response to food.

Work from our laboratory has shown that an enteric helminth infection can act as an adjuvant to prime for a Th2-biased response to a typically tolerogenic form of dietary antigen. Helminth infection did not, however, prime for an allergic response. Using a model in which systemic anaphylactic symptoms and antigen specific IgE are induced in C3H/HeJ mice by repeated intragastric administration of peanut antigen with the mucosal adjuvant cholera toxin we showed that an enteric helminth infection protects against the development of food allergy.

Mucosal immunity and allergic responses: lack of regulation and/or lack of microbial stimulation?

Allergic hyperreactivity is defined as an exaggerated immune response [typically immunoglobulin E (IgE) but also non-IgE mediated] toward harmless antigenic stimuli. The prevalence of allergic disease has increased dramatically during the last 20 years, especially in developed countries. Both genetic and environmental factors contribute to susceptibility to allergy.

Preventing intolerance: the induction of nonresponsiveness to dietary and microbial antigens in the intestinal mucosa.

The gut-associated lymphoid tissue (GALT) is constantly exposed to a variety of Ags and must therefore decipher a large number of distinct signals at all times. Responding correctly to each set of signals is crucial. When the GALT receives signals from the intestinal flora or food Ags, it must induce a state of nonresponsiveness (mucosal tolerance).

Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy.

The mechanisms by which signaling by the innate immune system controls susceptibility to allergy are poorly understood. In this report, we show that intragastric administration of a food allergen with a mucosal adjuvant induces allergen-specific IgE, elevated plasma histamine levels, and anaphylactic symptoms in three different strains of mice lacking a functional receptor for bacterial LPS (Toll-like receptor 4 (TLR4)), but not in MHC-matched or congenic controls. Susceptibility to allergy correlates with a Th2-biased cytokine response in both the mucosal (mesenteric lymph node and Peyer's patch) and systemic (spleen) tissues of TLR4-mutant or -deficient mice.

An enteric helminth infection protects against an allergic response to dietary antigen.

Although helminths induce a polarized Th2 response they have been shown, in clinical studies, to confer protection against allergies. To elucidate the basis for this paradox, we have examined the influence of an enteric helminth infection on a model of food allergy. Upon Ag challenge, mice fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine.

Man the barrier! Strategic defences in the intestinal mucosa.

Immunologists typically study the immune responses induced in the spleen or peripheral lymph nodes after parenteral immunization with antigen and poorly defined experimental adjuvants. However, most antigens enter the body through mucosal surfaces. It is now clear that the microenvironment in these mucosal barriers has a marked influence on the immune response that ultimately ensues.

Peripheral nonresponsiveness to orally administered soluble protein antigens.

The presentation of soluble model food antigens to the intestinal immune system typically induces antigen-specific systemic nonresponsiveness. Yet, the gut-associated lymphoid tissue (GALT) must launch an effective attack against potentially invasive pathogens even as it avoids mounting a response to innocuous food antigens. Although the mechanism by which the GALT is able to recognize and respond to these different forms of antigen is not clear, recent studies have shown that, initially, both tolerogenic and immunogenic forms of orally administered antigen elicit transient T-cell activation and proliferation.

Strain-specific TCR repertoire selection of IL-4-producing Thy-1 dull gamma delta thymocytes.

Thy-1 dull gamma delta thymocytes constitute an unusual subset of mature TCR gamma delta cells which share with NK T cells the expression of cell surface markers usually associated with activated or memory cells and the simultaneous production of high levels of IL-4 and IFN-gamma upon activation. In DBA / 2 mice, Thy-1 dull gamma delta thymocytes express a restricted repertoire of TCR that are composed of the V1 gene product mainly associated with V6.4 chains exhibiting very limited junctional sequence diversity.

Enteric infection acts as an adjuvant for the response to a model food antigen.

Oral administration of soluble protein Ags typically induces Ag-specific systemic nonresponsiveness. However, we have found that feeding a model food protein, OVA, to helminth-infected mice primes for a systemic OVA-specific Th2 response. In this report we show that, in addition to creating a Th2-priming cytokine environment, helminth infection up-regulates costimulatory molecule expression on mucosal, but not peripheral, APCs.

Tolerance and immunity in the intestinal immune system.

The intestinal immune system must guard the body against invasion by pathogens while avoiding a response to the many potential antigens present in food. In the absence of the inflammatory stimuli necessary to elicit an immune response, oral administration of soluble protein antigens induces antigen-specific systemic nonresponsiveness. Recent studies have shown that peripheral nonresponsiveness to orally administered antigen is preceded by transient T-cell activation and is due primarily to the induction of functional T-cell anergy.

Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy.

Helicobacter pylori is causally associated with gastritis and gastric cancer. Some developing countries with a high prevalence of infection have high gastric cancer rates, whereas in others, these rates are low. The progression of helicobacter-induced gastritis and gastric atrophy mediated by type 1 T-helper cells may be modulated by concurrent parasitic infection.

Orally induced peripheral nonresponsiveness is maintained in the absence of functional Th1 or Th2 cells.

Intragastric administration of soluble protein Ags results in peripheral tolerance to the fed Ag. To examine the role of cytokine regulation in the induction of oral tolerance, we fed OVA to mice deficient in Th1 (Stat 4-/-) and Th2 (Stat 6-/-) cells and compared their response to that of normal BALB/c controls. We found that, in spite of these deficiencies, OVA-specific peripheral cell-mediated and humoral nonresponsiveness was maintained in both Stat 4-/- and Stat 6-/- mice.

Oral administration of the bacterial superantigen staphylococcal enterotoxin B induces activation and cytokine production by T cells in murine gut-associated lymphoid tissue.

The toxicity of the staphylococcal enterotoxins (SEs) has been linked to the activation of large numbers of T cells in the peripheral lymphoid tissues. Because the primary manifestations of foodborne enterotoxic poisoning are associated with the gastrointestinal tract, we have compared the responses of T cells in the gut-associated lymphoid tissue and in the periphery to intragastric (i.g.

A helminth-induced mucosal Th2 response alters nonresponsiveness to oral administration of a soluble antigen.

A fascinating feature of the intestinal mucosal immune system is its ability to guard against invasion by pathogens while avoiding a response to the many potential Ags present in food. The phenomenon of systemic tolerance after oral administration of protein Ags is well documented, but the cellular and molecular basis for the observed nonresponsiveness is not fully understood. To gain insight into the role of the mucosal microenvironment in the induction of orally induced nonresponsiveness, we attempted to induce tolerance to OVA in mice primed for a Th2-biased mucosal immune response by infection with the nematode parasite Heligmosomoides polygyrus.

Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids.

Eotaxin is a potent and specific eosinophil chemoattractant that is mobilized in the respiratory epithelium after allergic stimulation. Pulmonary levels of eotaxin mRNA are known to increase after allergen exposure in sensitized animals. In this study we demonstrate that TNF alpha and IL-1beta induce the accumulation of eotaxin mRNA in the pulmonary epithelial cell lines A549 and BEAS 2B in a dose-dependent manner.

Cytokine imbalance and autoantibody production in T cell receptor-alpha mutant mice with inflammatory bowel disease.

Spontaneous inflammatory bowel disease (IBD) resembling human ulcerative colitis develops in mice mutant for the T cell receptor alpha gene (TCR-alpha-/-). TCR-alpha-/- mice lack TCR-alpha/beta+ cells but contain TCR-gamma/delta+ cells and a small population of a unique CD4+, TCR-alpha-/beta+(low) cells. Since all the immunoglobulin (Ig) classes are present in these mice, help to B cells must be provided by cells other than TCR-alpha/beta+ cells.

Most gamma delta T cells develop normally in the absence of MHC class II molecules.

MHC class I and class II molecules are essential for intrathymic maturation of a normal repertoire of alpha beta T cells. The development of gamma delta T cells may similarly require exposure to conventional MHC or MHC-like molecules for appropriate negative and positive selection. The availability of mice that are devoid of cell surface expression of MHC class II molecules allowed us to test directly the hypothesis that conventional class II molecules play a role in the development of gamma delta T cells.

Cytotoxic potential of intraepithelial lymphocytes (IELs). Presence of TIA-1, the cytolytic granule-associated protein, in human IELs in normal and diseased intestine.

Human intestinal intraepithelial lymphocytes (IELs) have phenotypic characteristics of cytotoxic T cells, yet a cytotoxic function has not been demonstrated in redirected lysis assays. A monoclonal antibody that reacts with a cytotoxic granule-associated protein, TIA-1, was used in this study to identify this protein in many, but not all, IELs of normal human proximal small intestine. Furthermore, in active celiac disease, in which the number of IELs is significantly increased, a corresponding increase in the number of TIA-1 cells was found.

Stimulation of murine intestinal intraepithelial lymphocytes by the bacterial superantigen staphylococcal enterotoxin B.

To gain insight into the specificity and function of intestinal intraepithelial lymphocytes (IEL), we have examined their response to staphylococcal enterotoxin B (SEB), a significant cause of food poisoning and a potent T cell mitogen. IEL include two populations of TCR alpha beta+ T cells. One of these resembles the T cells found in the Peyer's patch and is thymus dependent.

Self-reactive, T cell receptor-gamma delta+, lymphocytes from the intestinal epithelium of weanling mice.

Intraepithelial T lymphocytes (IEL) are dispersed throughout the intestinal epithelial lining but their role in cellular immune defense is unknown. Their location suggests that their highly activated state may be due to constant exposure to bacterial Ag. To study IEL specificity and function we have prepared a panel of IEL-T cell hybridomas from both adult and weanling C57B1/6 mice.