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Biomedical subjects

Nicola L Harris

Publications and source records attributed to Nicola L Harris.

13 recordsLinked to original sources
PubMed2006

Mechanisms of neonatal mucosal antibody protection.

Following an abrupt transition at birth from the sterile uterus to an environment with abundant commensal and pathogenic microbes, neonatal mammals are protected by maternal Abs at mucosal surfaces. We show in mice that different Ab isotypes work in distinct ways to protect the neonatal mucosal surface. Secretory IgA acts to limit penetration of commensal intestinal bacteria through the neonatal intestinal epithelium: an apparently primitive process that does not require diversification of the primary natural Ab repertoire. In contrast, neonatal protection against the exclusively luminal parasite Heligmosomoides polygyrus required IgG from primed females. This immune IgG could either be delivered directly in milk or retrotransported via neonatal Fc receptor from the neonatal serum into the intestinal lumen to exert its protective effect.

Animals↗
PubMed2006

IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo.

Interleukin 21 (IL-21) is a member of the common gamma-chain family of cytokines, which influence a broad spectrum of immunologic responses. A number of studies have examined the function of IL-21, but its specific role in Th1/Th2-cell differentiation and related effector responses remains to be clarified. Thus, we generated IL-21R-deficient mice and have investigated the role of IL-21R signaling using a series of in vivo experimentally induced disease models. We first addressed the role of IL-21R signaling in Th2 immune responses by examining allergic airway inflammation, and Nippostrongylus brasiliensis and Heligmosomoides polygyrus antihelminth responses. In each of these systems, IL-21R signaling played a clear role in the development of Th2 responses. Comparatively, IL-21R signaling was not required for the containment of Leishmania major infection or the development of experimental autoimmune myocarditis, indicative of competent Th1 and Th17 responses, respectively. Adoptive transfer of T cells and analysis of IL-21R+/+/IL-21R-/- chimera mice revealed that IL-21R-signaling was central to Th2-cell survival or migration to peripheral tissues. Overall, our data show IL-21 plays a crucial role in supporting polarized Th2 responses in vivo, while appearing superfluous for Th1 and Th17 responses.

Animals↗
PubMed2006

Natural IgE production in the absence of MHC Class II cognate help.

IgE induction by parasites and allergens is antigen driven and cognate T cell help dependent. We demonstrate that spontaneously produced IgE in T cell-deficient and germ-free wild-type (wt) mice is composed of natural specificities and induced by a mechanism independent of MHC class II (MHC II) cognate help. This does not require secondary lymphoid structures or germinal center formation, although some bystander T cell-derived IL-4 is necessary. The pathway of spontaneous IgE production is not inhibited by regulatory T cells and increases with age to constitute significant serum concentrations, even in naive animals.

Animals↗
PubMed2006

Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling.

The liver is known to be a classical immunoprivileged site with a relatively high resistance against immune responses. Here we demonstrate that highly activated liver-specific effector CD8+ T cells alone were not sufficient to trigger immune destruction of the liver in mice. Only additional innate immune signals orchestrated by TLR3 provoked liver damage. While TLR3 activation did not directly alter liver-specific CD8+ T cell function, it induced IFN-alpha and TNF-alpha release. These cytokines generated expression of the chemokine CXCL9 in the liver, thereby enhancing CD8+ T cell infiltration and liver disease in mice. Thus, nonspecific activation of innate immunity can drastically enhance susceptibility to immune destruction of a solid organ.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Requirement for neutralizing antibodies to control bone marrow transplantation-associated persistent viral infection and to reduce immunopathology.

Bone marrow transplantation (BMT) is commonly used in the treatment of leukemia, however its therapeutic application is partly limited by the high incidence of associated opportunistic infections. We modeled this clinical situation by infecting mice that underwent BMT with lymphocytic choriomeningitis virus (LCMV) and investigated the potential of immunotherapeutic strategies to counter such infections. All mice that received BMT survived LCMV infection and developed a virus carrier status. Immunotherapy by adoptive transfer of naive splenocytes protected against low (200 PFU), but not high (2 x 10(6) PFU), doses of LCMV. Attempts to control infection of high viral titers using strongly elevated frequencies of activated LCMV-specific T cells failed to control virus and resulted in immunopathology and death. In contrast, virus neutralizing Abs combined with naive splenocytes were able to efficiently control high-dose LCMV infection without associated side effects. Thus, cell transfer combined with neutralizing Abs represented the most effective means of controlling BMT-associated opportunistic viral infection in our in vivo model. These data underscore the in vivo efficacy and immunopathological "safety" of neutralizing antibodies.

Adoptive Transfer↗
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

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease.

Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8(+) T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-alpha production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.

Animals↗
PubMed2005

Inverse correlation between IL-7 receptor expression and CD8 T cell exhaustion during persistent antigen stimulation.

Persistence is a hallmark of infection by viruses such as HIV, hepatitis B virus, hepatitis C virus and LCMV. In the case of LCMV, persistence may often be associated with exhaustion of CD8(+) T cells. We demonstrate here that persistent antigen suppressed IL-7Ralpha expression and this correlated with T cell exhaustion and reduced expression of the anti-apoptotic molecule B cell leukemia/lymphoma 2 (Bcl-2). In contrast, exposure to short-lived antigen only temporarily suppressed IL-7Ralpha expression, failed to induce T cell exhaustion, and primed T cells. Persistent antigen also suppressed IL-7Ralpha expression on primed T cells and this correlated with exhaustion of a previously stable primed T cell population. These findings suggest that antigen longevity regulates T cell fate.

Animals↗
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

Deliberate removal of T cell help improves virus-neutralizing antibody production.

The B cell response to lymphocytic choriomeningitis virus is characterized by a CD4(+) T cell-dependent polyclonal hypergammaglobulinemia and delayed formation of virus-specific neutralizing antibodies. Here we provide evidence that, paradoxically, because of polyclonal B cell activation, virus-specific T cell help impairs the induction of neutralizing antibody responses. Experimental reduction in CD4(+) T cell help in vivo resulted in potent neutralizing antibody responses without impairment of CD8(+) T cell activity. These unexpected consequences of polyclonal B cell activation may affect vaccine strategies and the treatment of clinically relevant chronic bacterial, parasitic and viral infections in which hypergammaglobulinemia is regularly found.

Animals↗
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↗
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↗