Airway inflammation is believed to stimulate mucus production in asthmatic patients. Increased mucus secretion is an important clinical symptom and contributes to airway obstruction in asthma. Activated CD4 Th1 and Th2 cells have both been identified in airway biopsies of asthmatics but their role in mucus production is not clear. Using CD4 T cells from mice transgenic for the OVA-specific TCR, we studied the role of Th1 and Th2 cells in airway inflammation and mucus production. Airway inflammation induced by Th2 cells was comprised of eosinophils and lymphocytes; features found in asthmatic patients. Additionally, there was a marked increase in mucus production in mice that received Th2 cells and inhaled OVA, but not in mice that received Th1 cells. However, OVA-specific Th2 cells from IL-4–deficient mice were not recruited to the lung and did not induce mucus production. When this defect in homing was overcome by administration of TNF-α, IL-4 −/− Th2 cells induced mucus as effectively as IL-4 +/+ Th2 cells. These studies establish a role for Th2 cells in mucus production and dissect the effector functions of IL-4 in these processes. These data suggest that IL-4 is crucial for Th2 cell recruitment to the lung and for induction of inflammation, but has no direct role in mucus production.

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Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production

γδ T cells, αβ T cells, and B cells are present together in all but the most primitive vertebrates, suggesting that each population contributes to host immune competence uniquely and that all three are necessary for maintaining immune competence. Functional and molecular analyses indicate that in infections, γδ T cells respond earlier than αβ T cells do and that they emerge late after pathogen numbers start to decline. Thus, these cells may be involved in both establishing and regulating the inflammatory response. Moreover, γδ T cells and αβ T cells are clearly distinct in their antigen recognition and activation requirements as well as in the development of their antigen-specific repertoire and effector function. These aspects allow γδ T cells to occupy unique temporal and functional niches in host immune defense. We review these and other advances in γδ T cell biology in the context of their being the major initial IL-17 producers in acute infection.

γδ T cells: first line of defense and beyond.

Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells

Human Vgamma2Vdelta2 T cells play important roles in mediating immunity against microbial pathogens and have potent anti-tumor activity. Vgamma2Vdelta2 T cells recognize the pyrophosphorylated isoprenoid intermediates (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), an intermediate in the foreign 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway, and isopentenyl pyrophosphate (IPP), an intermediate in the self-mevalonate pathway. Infection with bacteria and protozoa using the MEP pathway leads to the rapid expansion of Vgamma2Vdelta2 T cells to very high numbers through preferential recognition of HMBPP. Activated Vgamma2Vdelta2 T cells produce proinflammatory cytokines and chemokines, kill infected cells, secrete growth factors for epithelial cells, and present antigens to alphabeta T cells. Vgamma2Vdelta2 T cells can also recognize high levels of IPP in certain tumors and in cells treated with pharmacological agents, such as bisphosphonates and alkylamines, that block farnesyl pyrophosphate synthase. Activated Vgamma2Vdelta2 T cells are able to kill most tumor cells because of recognition by T-cell receptor and natural killer receptors. The ubiquitous nature of the antigens converts essentially all Vgamma2Vdelta2 T cells to memory cells at an early age. Thus, primary infections with HMBPP-producing bacteria are perceived by Vgamma2Vdelta2 T cells as a repeat infection. Extensive efforts are underway to harness these cells to treat a variety of cancers and to provide microbial immunity.

Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vγ2Vδ2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens

MICA Engagement by Human Vγ2Vδ2 T Cells Enhances Their Antigen-Dependent Effector Function

T-lymphocytes with T-cell antigen receptor (TCR) comprising a γ chain and a δ chain (γδ+ T cells) are believed to be involved in the immune reaction to mycobacterial antigens, and they have been found in increased proportions in sarcoid patients. We evaluated the proportions of γδ+ T-lymphocytes and of two major γδ+ subpopulations, the Vδ1+ and the Vδ2+ T-cell subsets, in 10 normal blood donors, in 15 patients with tuberculosis (TB), seven of whom had pleural effusion (PE), and in 12 patients with pulmonary sarcoidosis (PS), nine of whom underwent bronchoalveolar lavage (BAL). T-cell subsets were evaluated in peripheral blood (PBL) of all subjects and in PE from patients with TB and in BAL from patients with PS. Compared with normal blood donors, patients with TB had increased proportions of PBL CD3+ γδ+ T cells (6 ± 1% versus 14 ± 3% of CD3+ T cells, p < 0.05) because of the presence of four patients who had an increase (respectively, 18.3, 22.0, 24.2, and 35.4% of CD3+ T cells) of γδ+ T cells. In patien...

T-Lymphocytes with γδ + Vδ2+ Antigen Receptors Are Present in Increased Proportions in a Fraction of Patients with Tuberculosis or with Sarcoidosis

HLA-DR class II molecules are expressed by a variety of nonlymphoid cells, including the respiratory epithelium. However, it is not known if ciliated bronchial epithelial cells express the HLA-DR genes, if the expression of class II molecules on their surface can be modulated by immune mediators and, finally, if these cells, like other HLA-DR-positive epithelial cells, have the potential to serve as antigen-presenting cells. To answer these questions, we collected ciliated bronchial epithelial cells by brushing and by suction during fiberoptic bronchoscopy and by scraping surgically resected bronchi. The number of cells recovered by brushing or suction during fiberoptic bronchoscopy was similar (P greater than 0.2), but lower than that obtained by scraping surgically resected bronchi (P less than 0.01); however, compared with brushing, suction of ciliated bronchial epithelial cells resulted in a better viability (P less than 0.05). HLA-DR antigens on ciliated bronchial epithelial cells were detected by immunofluorescence using the PTF 29.12 and the L243 monoclonal antibodies, both recognizing HLA-DR molecules on the vast majority of ciliated bronchial epithelial cells. Cytoplasmic dot blot analysis demonstrated that ciliated bronchial epithelial cells had mRNA HLA-DR transcripts, and Northern blot hybridizations showed that the size of the HLA-DR messages was the same observed in other HLA-DR-positive cells. Interestingly, ciliated bronchial epithelial cells showed a significant decline of HLA-DR expression after 5 days in culture, but the addition of gamma-interferon to the cell cultures was associated with the persistence of the expression of class II antigens on the cell surface (P less than 0.01 with control cultures at 5 days). Finally, while ciliated bronchial epithelial cells were ineffective in stimulating allogeneic T cell proliferation in a 6-day primary mixed leukocyte reaction (MLR), the addition of phorbol myristate acetate to the MLR was able to induce a significant T cell proliferation (P less than 0.001, all comparisons). Thus, human ciliated bronchial epithelial cells express HLA-DR surface antigens and have mRNA molecules for the HLA-DR genes, and the expression of the surface class II antigens can be modulated in vitro by immune mediators.(ABSTRACT TRUNCATED AT 400 WORDS)

Human Ciliated Bronchial Epithelial Cells: Expression of the HLA-DR Antigens and of the HLA-DR Alpha Gene, Modulation of the HLA-DR Antigens by Gamma-Interferon and Antigen-presenting Function in the Mixed Leukocyte Reaction

To evaluate the effects of thymomodulin (TMD), a thymic biological response modifier derived from calf thymus, on the release of various cytokines involved in the lung immune reactions, human alveolar macrophages (AM) and peripheral blood lymphocytes (PBL) were cultured either alone or in co-cultures. In co-cultures of AM with PBL, TMD did not induce any change in gamma-interferon (gamma-IFN) and interleukin-1 (IL-1) secretion, while it was able to increase the level, of tumour necrosis factor (TNF) (TMD 100 micrograms.m-1, p < 0.05 vs control cultures), and of granulocyte macrophage colony-stimulating factor (GM-CSF) (TMD 1, 10 and 100 micrograms.ml-1 p < 0.05, < 0.05 and < 0.01, respectively, vs control cultures). In cultures of AM alone, TMD did not induce changes in the levels of any of the tested cytokines, whilst in supernatants from PBL lymphocyte cultures, TMD at 1, 10 and 100 micrograms.ml-1 increased the amounts of GM-CSF (p < 0.01 each comparison vs control cultures). Thus, TMD seems to directly stimulate lymphocytes to secrete GM-CSF and to modulate macrophage-lymphocyte interactions, resulting in the release of TNF and GM-CSF.

https://erj.ersjournals.com/content/erj/5/9/1097.full.pdf

Thymomodulin increases release of granulocyte-macrophage colony stimulating factor and of tumour necrosis factor in vitro

Thymomodulin (TMD), a thymic biological response modifier, stimulates the release of tumour necrosis factor (TNF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) in macrophage-lymphocyte cultures. We investigated the effects of the cytokines released in cultures with TMD, on the expression of human leucocyte antigen-DR (HLA-DR) antigens by alveolar macrophages (AM) and the T-cell proliferation induced in autologous mixed leucocyte reaction (AMLR) cultures or by T-cell mitogens. Among freshly isolated AM, 84 +/- 4% were HLA-DR positive, and this proportion was significantly reduced after 24 h cultures (60 +/- 3%, p < 0.05). In cultures without peripheral blood (PBL) lymphocytes, TMD did not change HLA-DR expression by AM CHLA-DR+AM); whilst in the presence of autologous PBL lymphocytes, TMD induced an increase in the proportions of HLA-DR+AM (TMD 100 micrograms.ml-1 79 + 3%, p < 0.04 vs control cultures). However, TMD did not change the ability of AM to induce T-cell proliferation in AMLR between AM and PBL lymphocytes. In contrast, in PBL mononuclear cell cultures, TMD induced a further increase of the cell proliferation due to the T-cell mitogens interleukin-2 (IL-2) or phytohaemagglutinin (PHA) (p < 0.05 vs each control culture with mitogens) or anti-CD3 antibodies (p < 0.03 vs control cultures). Thus, the cytokines released in cultures with TMD enhance macrophage HLA-DR expression. Whilst this phenomenon is not associated with changes in the ability of AM to stimulate T-cell proliferation, TMD is able to increase the mitogen-induced T-cell proliferation.

https://erj.ersjournals.com/content/erj/6/1/102.full.pdf

Luigi Allegra

Papers

T-Lymphocytes with γδ + Vδ2+ Antigen Receptors Are Present in Increased Proportions in a Fraction of Patients with Tuberculosis or with Sarcoidosis

Human Ciliated Bronchial Epithelial Cells: Expression of the HLA-DR Antigens and of the HLA-DR Alpha Gene, Modulation of the HLA-DR Antigens by Gamma-Interferon and Antigen-presenting Function in the Mixed Leukocyte Reaction

Thymomodulin increases release of granulocyte-macrophage colony stimulating factor and of tumour necrosis factor in vitro

Thymomodulin increases HLA-DR expression by macrophages but not T-lymphocyte proliferation in autologous mixed leucocyte reaction

H2O2 Production and Cytotoxic Activity of Peripheral Blood Human Eosinophils following Stimulation with IgG and IgE Immune Complexes1