Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2 memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2CD161CD45ROCD4 Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.
One basic attribute of lymphocytes is their ability to recognize self from nonself. Lymphoblastoid transformation and the associated [3H]thymidine incorporation in in vitro cultures of lymphocytes is generally recognized as a response to nonself antigens . We report here on the surprising finding that in vitro stimulation occurs among autologous lymphocytes in the mixed lymphocyte culture (MLC) test. The most likely explanation of our findings is that among lymphocytes obtained from one sample of peripheral blood, thymus-derived (T) lymphocytes respond against non-T cells in the autologous mixed lymphocyte culture (AMLC) reaction . Materials and MethodsBrief Definitive Report Lymphocyte Fractionation. Peripheral blood lymphocytes containing less than 5% granulocytes were isolated by Ficoll-Hypaque gradient centrifugation . The blood donors were healthy volunteers between 20 and 30 yr of age. Assessment of T cells and bone-marrow-derived (B) cells and fractionation of lymphocyte suspensions into T-rich and 13-rich subpopulations by the sheep red blood cell (SRBC) rosetting technique and by goat-antihuman immunoglobulin column fractionation was done as described (1). Whereas unfractionated lymphocyte suspensions contained 70 2% (mean ± SE) T cells and 19 ± 2% B cells, the respective percentages after fractionation by the SRBC rosetting technique in 11 experiments were 92 ± 1% and 6 -1% for the T-rich fractions and 29 -5% and 51 ± 4% for the B-rich fractions. Passage of lymphocytes through goat-antihuman immunoglobulin-coated columns did not increase the percentage of T cells equally well (80 -2%), but reduced the percentage of B cells to 4 -1% .Mixed Lymphocyte Culture . MLC were done as described by micromethods using 5 x 10°r esponding cells and 5 x 10°irradiated stimulating cells in a total volume of 0.1 ml (2). All cultures were done in triplicate. Uptake of [3H]thymidine was measured by liquid scintillation spectrophotometry, and counts per minute given are the mean cpm of the triplicate cultures ± SE . Stimulation ratios were calculated by dividing the mean counts per minute of a given experiment by the mean counts per minute of the responding cell's background control culture. ResultsThe general outline of the experiments was to recombine the separated T-rich and 13-rich fractions of lymphocytes in a checkerboard fashion. One representative experiment is given in Table I. In the first line, it can be noted that the unfractionated lymphocytes respond strongly to autologous B-rich cells. The
When effector lymphocytes were reacted with cultured human tumors, the total cytotoxic reaction could be divided into selective and nonselective components. The nonselective part of the reaction was due to a cell type called N cells. Fractionation of effector suspension indicated that N cells were neither T nor B cells. Like B cells, N cells did not form rosettes with sheep erythrocytes; they were retained by columns coated with lg or antiserum to lg and died preferentially when stored at an ambient temperature. However, N cells were differentiated from B cells by their inability to form complement-receptor rosettes and by their survival when incubated at 30 degrees C. The effect of the nonselective cytotoxic cell must be differentiated from selective activity in studies of specificity for cell-mediated cytotoxicity.
Oral immunotherapy (OIT) is an effective approach to controlling food allergy. Although the detailed molecular and cellular mechanisms of OIT are unknown currently, they must be understood to advance the treatment of allergic diseases in general. To elucidate the mechanisms of OIT, especially during the immunological transition from desensitization to allergy regulation, we generated a clinical OIT murine model and used it to examine immunological events of OIT. We found that in mice that completed OIT successfully, desensitized mast cells (MCs) showed functionally beneficial alterations, such as increased induction of regulatory cytokines and enhanced expansion of regulatory T cells. Importantly, these regulatory-T-cell-mediated inhibitions of allergic responses were dramatically decreased in mice lacking OIT-induced desensitized MC. Collectively, these findings show that the desensitization process modulates the activation of MCs, leading directly to enhanced induction of regulatory-T-cell expansion and promotion of clinical allergic unresponsiveness. Our results suggest that efficiently inducing regulatory MCs is a novel strategy for the treatment of allergic disease.
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