T cells expressing NK cell receptors (NKR) display rapid MHC-unrestricted cytotoxicity and potent cytokine secretion and are thought to play roles in immunity against tumors. We have quantified and characterized NKR + T cells freshly isolated from epithelial and lamina propria layers of duodenum and colon from 16 individuals with no evidence of gastrointestinal disease and from tumor and uninvolved tissue from 19 patients with colorectal cancer. NKR + T cell subpopulations were differentially distributed in different intestinal compartments, and CD161 + T cells accounted for over one half of T cells at all locations tested. Most intestinal CD161 + T cells expressed § g TCR and either CD4 or CD8. Significant proportions expressed HLA-DR, CD69 and Fas ligand. Upon stimulation in vitro, CD161 + T cells produced IFN-+ and TNF- § but not IL-4. NKT cells expressing the V § 24V g 11 TCR, which recognizes CD1d, were virtually absent from the intestine, but colonic cells produced IFN-+ in response to the NKT cell agonist ligand § -galactosylceramide. NKR + T cells were not expanded in colonic tumors compared to adjacent uninvolved tissue. The predominance, heterogeneity and differential distribution of NKR + T cells at different intestinal locations suggests that they are central to intestinal immunity.
Multiple sclerosis (MS) is an autoimmune disorder characterised by clinical relapse and remission and pathological demyelination with varying inflammation. Because it is suggested that T-cells expressing natural killer cell receptors (NKR) play important roles in regulating human autoimmune diseases, we have quantified populations T-cells expressing the NKR CD56, CD161 and CD94 in the peripheral blood of MS patients, in healthy control subjects (HS) and in patients with other neurological diseases (OND). CD161 + T-cells and CD94 + T-cells were significantly decreased in MS patients with primary progressive disease and secondarily change progressive disease respectively whereas CD56 + T-cell numbers were unchanged. In contrast NKT-cells that express the invariant V α 24-J α 18 + T-cell receptor identified here by specific receptor antibody and CD1d-tetrameric PBS57-loaded complexes, were increased in MS patients compared with HS. Reductions in CD161 + T-cells and CD94 + T cells relative to HS were also observed in the OND group and this was particularly prominent in Parkinsonian patients. A striking functional finding was that while NKT-cells in unfractionated peripheral blood from healthy subjects expanded in number and produced IFN-γ upon stimulation with α-galactosylceramide, NKT-cells from MS patients did not. Thus we have identified alterations in a number of potentially important lymphocyte sub-populations warranting further investigation in the immune response in MS.
Infection by the gastroduodenal pathogen Helicobacter pylori elicits a complex immunologic response in the mucosa involving neutrophils, plasma cells, eosinophils, and lymphocytes, of which T cells are the principal orchestrators of immunity. While so-called classical T cells (e.g. T-helper cells) that are activated by peptide fragments presented on antigen-presenting cells have received much attention in H. pylori infection, there exists a diverse array of other T cell populations that are potentially important for the outcome of the ensuing immune response, some of which have not been extensively studied in H. pylori infection. Pathogen-specific regulatory T cells that control and prevent the development of immunopathology associated with H. pylori infection have been investigated, but these cells can also benefit the bacterium in helping to prolong the chronicity of the infection by suppressing protective immune responses. An overlooked T cell population, the more recently described Th17 cells, may play a role in H. pylori-induced inflammation, due to triggering responses that ultimately lead to the recruitment of polymorphs, including neutrophils. The so-called innate or unconventional T cells, that include two conserved T cell subsets expressing invariant antigen-specific receptors, the CD1d-restricted natural killer T cells which are activated by glycolipids, and the mucosal-associated invariant T cells which play a role in defense against orally acquired pathogens in the intestinal mucosa, have only begun to receive attention. A greater knowledge of the range of T cell responses induced by H. pylori is required for a deeper understanding of the pathogenesis of this bacterium and its ability to perpetuate chronic infection, and could reveal new strategies for therapeutic exploitation.
The immune response of PBMC to gliadin was investigated in patients with coeliac disease (CoD) by examining proliferation, MHC restriction and cytokine production. Gliadin induced low levels of proliferation in 63% of eight untreated patients, 32% of 28 treated patients and 35% of 31 healthy control subjects. In MHC restriction studies, the proliferative response to gliadin was inhibited (range 47-98% inhibition) in the presence of a MoAb to HLA-DR in each of three coeliac and three control donors studied. Using flow cytometry, increased expression of activation markers (HLA-DR and IL-2R) was demonstrated on gliadin-stimulated T cells from four of nine coeliac patients and three of seven healthy control donors. Cytokines were studied in culture supernatants using ELISA. Gliadin was a potent inducer of IL-6 and IL-10 in 100% of coeliac patients and controls, whereas IL-4 was not produced in either subject group. Gliadin induced IL-2 production in 40% of untreated patients, 42% of treated patients and 35% of healthy control donors. Interferon-gamma (IFN-gamma) in gliadin-stimulated cultures was found only in coeliac patients, observed in 33% of untreated patients and 25% of treated patients. Spontaneous secretion of both IL-2 and IFN-gamma was found more frequently in patients with untreated disease (87% of cases versus 21% of controls for IFN-gamma and 40% versus 0% for IL-2). These results suggest, as manifest by IFN-gamma production, that gliadin stimulates a Th1/Th0-like response in coeliac patients and a Th0-like response in healthy controls.
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