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Graham Le Gros

Publications and source records attributed to Graham Le Gros.

15 recordsLinked to original sources
PubMed2007

Induction of Th2 type immunity in a mouse system reveals a novel immunoregulatory role of basophils.

While production of cytokines such as IL-12 by activated dendritic cells supports development of Th1 type immunity, a source of early IL-4 that is responsible for Th2 immunity is not well understood. We now show that coculture of basophils could promote a robust Th2 differentiation upon stimulation of naive CD4 T cells primarily via IL-4. Th2 promotion by basophils was also observed even when naive CD4 T cells were stimulated in a Th1-promoting condition or when fully differentiated Th1 phenotype effector CD4 T cells were restimulated. IL-4-deficient basophils failed to induce Th2 differentiation but suppressed Th1 differentiation. It was subsequently revealed that the IL-4-deficient basophils must engage cell-to-cell contact to exert the inhibitory effect on Th1 differentiation. Stimulation of naive CD4 T cells within an in vivo environment of increased basophil generation supported development of Th2 type immunity. Taken together, our results suggest that basophils may provide an important link for the development of Th2 immunity.

Animals↗
PubMed2006

Critical role of preproenkephalin in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an organ-specific autoimmune disease model used to investigate mechanisms involved in the activation of self-reactive T cells. Preproenkephalin (PPNK) is the gene that encodes the protein proenkephalin A that has been detected in the brain, adrenal cells and cells of the immune system. In this paper, whether PPNK plays a role in the development of EAE was investigated. PPNK-deficient and wild-type mice were immunized with the MOG(35-55) peptide and the development of EAE observed. Our results show that PPNK-deficient mice developed less severe clinical signs of disease than wild-type mice, and with lower incidence. MOG(35-55)-specific T cells from PPNK-deficient and wild-type mice produced IFNgamma and TNFalpha but no IL-4 or IL-10, indicative of a Th1 phenotype. However, the numbers of MOG(35-55)-specific IFNgamma-producing cells from immunized PPNK-deficient mice were largely reduced at early stages of disease. Interestingly, there was no difference in clinical signs or infiltrating mononuclear cells in the CNS between wild-type and PPNK-deficient mice at the later stage of disease. Our results suggest that PPNK accelerates the generation of autoimmune IFNgamma-producing T cells and MOG(35-55)-induced EAE.

Animals↗
PubMed2006

Basophils: a potential liaison between innate and adaptive immunity.

Activation of innate immunity is closely associated to development of protective adaptive immune response. Significant advances have been made to reveal such links between innate immunity and Th1 type adaptive immune responses. By contrast, the role of innate immunity in the development of Th2 type adaptive immune responses is still not well understood. Production of IL-4, a key cytokine in the induction of Th2 immunity, by innate type cells represents an attractive mechanism for such an innate link to Th2 immunity. We have recently reported that in the course of infection with the intestinal nematode, Nippostrongylus brasiliensis, a robust basophil accumulation in the liver/spleen occurs and that these basophils display enhanced IL-4 production. Thus, the basophils is an attractive candidate to mediate the innate-adaptive link for Th2 responses and understanding the control of the tissue homing patterns and cytokine responses of basophils in the course of infections may shed important light on the in vivo induction of Th2 adaptive immunity.

Animals↗
PubMed2005

Nuclear factor of activated T (NFAT) cells activity within CD4+ T cells is influenced by activation status and tissue localisation.

Nuclear factor of activated T (NFAT) cells is a family of transcription factors important for the regulation of cytokine expression by CD4+ T cells. Whilst a number of studies have examined NFAT activity of in vitro generated CD4+ T helper (Th)1 and Th2 cells, regulation of NFAT during in vivo immune responses has yet to be elucidated. We show that NFAT activity in CD4+ T cells peaked at early time-points in the draining mediastinal lymph node of mice infected with influenza A (Flu) or Nippostrongylus brasiliensis (Nb). In contrast, low NFAT transcriptional activity was detected in CD4+ T cells isolated from the lung of either Flu or Nb infected mice, despite a greater proportion of cytokine-producing cells being present at this site. These findings indicate that the activation status and tissue microenvironment of effector CD4+ T cells can determine their requirement for NFAT-mediated transcription.

Animals↗
PubMed2005

Effector lymphoid tissue and its crucial role in protective immunity.

It is often argued that T cell-mediated immunity to secondary infection is dependent on the 'accelerated' responses of memory T cells in lymph nodes. However, new evidence points to a crucial role for effector memory T cells, which are resident in peripheral tissues, in immune protection. These T cells, which reside in peripheral tissues, are not necessarily bound by an anatomical structure and can be present at many sites. Collectively, they represent a third functional tissue of the immune system, uniquely specialized to mediate protective immunity. We propose that the paradigm 'effector lymphoid tissue' needs to be articulated and developed as a focus of new research to describe and understand the unique role this tissue has in protective immunity.

Animals↗
PubMed2005

Secretory products from infective forms of Nippostrongylus brasiliensis induce a rapid allergic airway inflammatory response.

Allergic asthma is responsible for widespread morbidity and mortality and its incidence has increased dramatically in industrialized countries over the past two decades. Here, we describe a new murine model of allergic asthma utilizing a novel allergen with intrinsic enzymatic activity similar to that reported for many environmental allergens. The allergen, NES, is excreted and secreted from the nematode Nippostrongylus brasiliensis, and can readily be isolated from in vitro parasite cultures. When NES is administered intranasally to presensitized mice, allergic airway disease develops, including airway hyper-responsiveness, airway eosinophilia, IgE antibody production and Th2 cytokine production. This disease is characteristic of atopic asthma and can be induced within 11 days, thus providing a platform for the rapid analysis of allergic disease and high throughput testing of immunomodulatory factors.

Allergens↗
PubMed2005

Tissue localization and frequency of antigen-specific effector CD4 T cells determines the development of allergic airway inflammation.

Previous activation of effector Th2 cells is central to the development of allergic inflammatory responses. We have observed that priming of allergen-specific Th2 cells in C57BL/6 or B10.A mice with allergen delivered via the i.p. or s.c. routes results in very different outcomes following subsequent airway exposure to the same allergen. Systemic allergen immunization (via the i.p. route) resulted in the formation of a lung-resident population of allergen-specific T cells, and mice developed severe allergic airway inflammation in response to inhaled allergen. The localization of cells to the lung did not require the presence of antigen at this site, but reflected a large pool of circulating activated allergen-specific T cells. In contrast, localized immunization (via the s.c. route) resulted in a small T-cell response restricted to the draining lymph node, and mice were not responsive to inhaled allergen. These data indicate that prior sensitization to an allergen alone was not sufficient for the induction of allergic inflammation; rather, responsiveness was largely determined by precursor frequency and tissue localization of the allergen-specific effector Th2 cells.

Amino Acid Sequence↗
PubMed2004

Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells.

CD8+ memory T cells have recently been recognized as playing a key role in natural immunity against unrelated viral infections, a phenomenon referred to as "heterologous antiviral immunity." We now provide data that the cellular immunological interactions that underlie such heterologous immunity can play an equally important role in regulating T helper 2 immune responses and protecting mucosal surfaces from allergen-induced inflammation. Our data show that CD8+ T cells, either retained in the lung after infection with influenza virus, or adoptively transferred via the intranasal route can suppress allergic airway inflammation. The suppression is mediated by IFN-gamma, which acts to reduce the activation level, T helper 2 cytokine production, airways hyperresponsiveness, and migration of allergen-specific CD4+ T cells into the lung, whereas the systemic and draining lymph node responses remain unchanged. Of note, adoptive transfer of previously activated transgenic CD8+ T cells conferred protection against allergic airway inflammation, even in the absence of specific-antigen. Airway resident CD8+ T cells produced IFN-gamma when directly exposed to conditioned media from activated dendritic cells or the proinflammatory cytokines IL-12 and IL-18. Taken together these data indicate that effector/memory CD8+ T cells present in the airways produce IFN-gamma after inflammatory stimuli, independent of specific-antigen, and as a consequence play a key role in modifying the degree and frequency of allergic responses in the lung.

Adoptive Transfer↗
PubMed2004

Suppression of allergic airway disease using mycobacterial lipoglycans.

BACKGROUND: Administration of heat-killed mycobacteria can suppress allergic disease in mice and humans. The active components of mycobacteria mediating these effects remain unresolved. OBJECTIVE: We sought to identify the active components of mycobacteria mediating suppression of allergic disease and to determine structural features important for function. METHODS: Using a murine model of allergic airway disease, we tested the ability of the lipoglycan fractions of the mycobacterial cell wall to suppress airway eosinophilia. Lipoglycans isolated from different strains of mycobacteria and chemical modifications were used to explore structure-function relationships. Markers of allergic disease including bronchoalvealor lavage cytokines, spleen and lymph node T-cell cytokine production, and serum specific immunoglobulin (Ig) E/IgG1 were examined. RESULTS: We identified the mycobacterial cell wall lipoglycans lipoarabinomannan and phosphatidylinositol mannan as components of mycobacteria capable of suppressing airway disease (>70% reduction in airway eosinophilia; P <.03). Structure-function analysis identified the acyl chains and mannose groups of the molecules as having a role in mediating this effect. Mechanistic studies provided no evidence for a T-helper cell (Th) 1-mediated suppression of an ongoing Th2 response. An increased capacity of T cells to secrete interleukin 10 in the spleen and lymph node of treated animals was identified, suggesting a potential T-cell-mediated suppression mechanism. CONCLUSION: We have identified immunomodulatory component(s) of mycobacteria responsible for the protective effects observed in allergic disease; these findings will lead to the generation of synthetic compounds or agonists devoid of the unwanted characteristics of whole mycobacteria for evaluation in a human clinical setting.

Animals↗
PubMed2004

Can bacterial endotoxin exposure reverse atopy and atopic disease?

Studies have shown that endotoxin exposure in childhood is associated with a reduced risk of atopy and atopic asthma. It is commonly assumed that these effects only occur in early life. However, recent epidemiologic studies suggest that immune deviation might take place throughout life. Assuming that the immune system is not fixed after the first years of life, we hypothesize that endotoxin exposure might not only inhibit the development of atopic sensitization and disease at any time throughout life but might also reverse this process. This novel extension of the hygiene hypothesis is primarily based on the indirect evidence of several epidemiologic observations showing a reduction in atopy in adults highly exposed to endotoxin that is unlikely to be explained by protective effects alone. In addition, some animal studies demonstrated the potential of endotoxin to downregulate pre-existing airway eosinophilia and hyperreactivity. However, there is currently little direct evidence that endotoxin might reverse atopy and allergic diseases. Observational studies and randomized trials to test this hypothesis could ultimately lead to the development of novel treatments for atopic diseases, such as allergic asthma, hay fever, and eczema.

Bronchial Hyperreactivity↗
PubMed2003

CD8+ T cells and immunoregulatory networks in asthma.

It is well established that infection with respiratory viruses can cause acute local inflammation in humans and is a leading cause in the hospitalization of asthmatics. Less well recognized is the potential for viral infections to actually protect against the development of asthma, as are the cellular mechanisms which might underlie such protection. This review outlines the basic immunological pathways involved in atopic asthma and details the currently recognized cellular mechanisms induced by respiratory viral infections which can protect against the development of asthma. Specifically, it appears that virus infection induced memory T cells that remain in tissues, e.g. the lung and airways, can under certain circumstances create a local cytokine milieu which inhibits the development of ensuing allergic immune responses at that site. One key aspect of this immune modulation is the cytokine-dependent communication which occurs between the innate and the adaptive immune systems. The mechanistic principles underlying this form of immunomodulation should be taken into consideration when developing future forms of therapy and rational vaccine design.

Adjuvants, Immunologic↗
PubMed2003

Absence of preproenkephalin increases the threshold for T cell activation.

Certain forms of the neuroendocrine hormone preproenkephalin (PPNK) are produced by T cells, B cells and macrophages. This hormone has been shown to be important in regulating a variety of immune responses; however, the basic mechanisms of this regulation are unknown. Here we examine the ability of CD8 and CD4 PPNK-deficient T lymphocytes to proliferate to antigenic and mitogenic stimuli. We found that lymphocyte activation and proliferation to suboptimal concentrations of both anti-CD3 and antigen was reduced in the absence of PPNK. Proliferation could be rescued by increasing antigen or by co-incubation of PPNK-deficient cells with wild-type cells. These data confirm the importance of neuroendocrine hormones such as PPNK in T cell activation and proliferation and provides a potential mechanism for the regulation of T cell responses by PPNK or its peptide derivatives.

Animals↗
PubMed2002

c-Jun NH(2)-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation.

The c-Jun NH(2)-terminal kinase (JNK) signaling pathway is induced by cytokines and stress stimuli and is implicated in cell death and differentiation, but the specific function of this pathway depends on the cell type. Here we examined the role of JNK1 and JNK2 in CD8(+) T cells. Unlike CD4(+) T cells, the absence of JNK2 causes increased interleukin (IL)-2 production and proliferation of CD8(+) T cells. In contrast, JNK1-deficient CD8(+) T cells are unable to undergo antigen-stimulated expansion in vitro, even in the presence of exogenous IL-2. The hypoproliferation of these cells is associated with impaired IL-2 receptor alpha chain (CD25) gene and cell surface expression. The reduced level of nuclear activating protein 1 (AP-1) complexes in activated JNK1-deficient CD8(+) T cells can account for the impaired IL-2 receptor alpha chain gene expression. Thus, JNK1 and JNK2 play different roles during CD8(+) T cell activation and these roles differ from those in CD4(+) T cells.

Animals↗
PubMed2002

Differential T cell function and fate in lymph node and nonlymphoid tissues.

The functions and fate of antigen-experienced T cells isolated from lymph node or nonlymphoid tissues were analyzed in a system involving adoptive transfer of in vitro-activated T cells into mice. Activated T cells present in the lymph nodes could be stimulated by antigen to divide, produce effector cytokines, and migrate to peripheral tissues. By contrast, activated T cells that had migrated into nonlymphoid tissues (lung and airway) produced substantial effector cytokines upon antigen challenge, but were completely unable to divide or migrate back to the lymph nodes. Therefore, activated T cells can undergo clonal expansion in the lymph node, but are recruited and retained as nondividing cells in nonlymphoid tissues. These distinct regulatory events in lymph node and nonlymphoid tissues reveal simple key mechanisms for both inducing and limiting T cell immunity.

Adoptive Transfer↗