Th1-polarized Response Research Articles

Alveolar macrophages control the quality of CD4+ T lymphocytes in the respiratory tract upon recombinant adenoviral mucosal vaccination (39.34)

Abstract Infectious diseases are acquired through mucosa surfaces making mucosal vaccination important for their control. Previously, using a recombinant adenoviral-based (Ad) vaccine we have demonstrated that a single mucosal but not parenteral immunization confers protection against intracellular bacterial challenge in the lung. Here, we examined the mechanisms regulating induction of OVA-specific CD4 T-cell responses at mucosal and systemic compartments in Balb/C mice after intranasal (i.n.) or intramuscular (i.m.) vaccination with an Ad expressing OVA. We found that i.n. vaccination induced local OVA-specific T cell activation whereas i.m. vaccination induced both local and systemic T-cell activation despite of the dosage used for vaccination. Remarkably, i.n. immunization induced a characteristic proliferative kinetic different from the one induced by i.m. vaccination. Furthermore, i.n. vaccination induced a highly polarized Th1 response while i.m. immunization induced a mixed Th1/Th2 response. Of importance, in vivo depletion of alveolar macrophages led to similar T-cell proliferation kinetics and comparable cytokine production in mice receiving i.n. and i.m. vaccination. Our data suggests that alveolar macrophages provide a special microenvironment at the mucosal site, which control the quantity and quality of CD4 T memory cells and protective immunity against mucosal infectious challenges.

Galectin-3 Is Critical for the Development of the Allergic Inflammatory Response in a Mouse Model of Atopic Dermatitis

Galectin-3 belongs to a family of beta-galactoside-binding animal lectins expressed in several cell types, including epithelial and immune cells. To establish the role of galectin-3 in the development of allergic skin inflammation, we compared inflammatory skin responses of galectin-3-deficient (gal3(-/-)) and wild-type (gal3(+/+)) mice to epicutaneous sensitization with ovalbumin (OVA). OVA-treated gal3(-/-) mice exhibited markedly reduced epidermal thickening, lower eosinophil infiltration, and lower serum IgE levels compared with gal3(+/+) mice. The former evoked lower interleukin-4, but higher interferon-gamma, mRNA expression at OVA-treated skin sites. Moreover, gal3(-/-) splenocytes from OVA-sensitized mice secreted more interleukin-12 compared with gal3(+/+) splenocytes. In addition, antigen presentation by gal3(-/-) dendritic cells to T cells in vitro were T helper cell (Th1)-polarized relative to presentation by gal3(+/+) dendritic cells. When exposed to OVA, recipients engrafted with T cells from gal3(-/-) OVA-specific T cell receptor transgenic mice developed significantly reduced dermatitis and a markedly lower Th2 response compared with recipients of comparable gal3(+/+) T cells. We conclude that galectin-3 is critical for the development of inflammatory Th2 responses to epicutaneously administered antigens; in its absence, mice develop a Th1-polarized response. This regulatory effect of galectin-3 on Th development is exerted at both the dendritic cell and T cell levels. Our studies suggest that galectin-3 may play an important role in the acute phase of human atopic dermatitis.

Helicobacter pylori-Induced Interleukin-12 p40 Expression

Interleukin-12 (IL-12) is a heterodimeric cytokine produced by antigen-presenting cells that promotes the development of T-helper lymphocyte 1 (Th1). Chronic gastritis induced by Helicobacter pylori is considered a Th1-mediated process. IL-12 levels in gastric biopsy samples of H. pylori-infected patients are higher than in those of uninfected individuals, but the cellular source of IL-12 remains elusive. IL-12 staining was detected in mucosal epithelial cells, lymphocytes, and macrophages in specimens of patients with H. pylori-positive gastritis. Therefore, we investigated IL-12 p40 mRNA induction by H. pylori in gastric epithelial cells and T cells. Although cag pathogenicity island (PAI)-positive H. pylori induced IL-12 p40 mRNA expression, an isogenic mutant of the cag PAI failed to induce it in both cell types. Supernatants from H. pylori cultures and H. pylori VacA induced IL-12 p40 mRNA expression in T cells but not in epithelial cells. The activation of the IL-12 p40 promoter by H. pylori was mediated through NF-kappaB. The transfection of IkappaB kinase and NF-kappaB-inducing kinase dominant-negative mutants inhibited H. pylori-induced IL-12 p40 activation. Inhibitors of NF-kappaB, phosphatidylinositol 3-kinase, p38 mitogen-activated protein kinase, and Hsp90 suppressed H. pylori- and VacA-induced IL-12 p40 mRNA expression. The results indicate that H. pylori induces IL-12 p40 expression by the activation of NF-kappaB, phosphatidylinositol 3-kinase, and p38 mitogen-activated protein kinase. Hsp90 is also a crucial regulator of H. pylori-induced IL-12 p40 expression. In addition to the cag PAI, VacA might be relevant in the induction of IL-12 expression and a Th1-polarized response only in T cells.

KMP-11 DNA immunization significantly protects against L. donovani infection but requires exogenous IL-12 as an adjuvant for comparable protection against L. major

As vaccine potential of cross-species protection by a candidate antigen is less explored, in this study we compared cross-specific protective efficacy of Kinetoplastid Membrane Protein-11 (KMP-11) as a DNA vaccine alone and in conjunction with exogenous IL-12 administration in experimental BALB/c model against two most widely prevalent forms of clinical diseases caused by Leishmania major (LM) and Leishmania donovani (LD). Whereas, KMP-11 DNA vaccination alone showed significant potential in terms of resolution of splenic and hepatic parasite burden against virulent LD challenge, it showed considerably less efficacy (<70% reduction) against virulent LM challenge in terms of presence of parasite in lymph node. Remarkably exogenous IL-12 administration in the form of IL-12 p35/p40 expression vectors or recombinant protein along with KMP-11 DNA had exactly opposing effect on protection against LM and LD. Exogenous IL-12 administration significantly increased residual LD-burden but enhanced the protective efficacy of KMP-11 DNA vaccine against LM compared to KMP-11 immunization alone. Elucidation of effector mechanism showed KMP-11 DNA induced protection against LD was associated with the generation of mixed Th1/Th2 response, while KMP-11/IL-12-induced comparable protection against LM was associated with high IgG2a titre indicative of a polarized Th1 response. Exogenous IL-12 administration resulted in robust gamma interferon (IFN-γ) production and suppression of IL-4 from CD4+ T cell against both LM and LD. Nevertheless protective immune response was only compromised against LD infection where frequency of anti-KMP-11 CTL response was significantly reduced after exogenous IL-12 administration. Our study provides a comparative evaluation of effector mechanisms in the assessment of cross-specific protection by KMP-11 and KMP-11/IL-12 immunization against these two prevalent forms of leishmaniasis.

Allergen Uptake, Activation, and IL-23 Production by Pulmonary Myeloid DCs Drives Airway Hyperresponsiveness in Asthma-Susceptible Mice

Maladaptive, Th2-polarized inflammatory responses are integral to the pathogenesis of allergic asthma. As regulators of T cell activation, dendritic cells (DCs) are important mediators of allergic asthma, yet the precise signals which render endogenous DCs “pro-asthmatic”, and the extent to which these signals are regulated by the pulmonary environment and host genetics, remains unclear. Comparative phenotypic and functional analysis of pulmonary DC populations in mice susceptible (A/J), or resistant (C3H) to experimental asthma, revealed that susceptibility to airway hyperresponsiveness is associated with preferential myeloid DC (mDC) allergen uptake, and production of Th17-skewing cytokines (IL-6, IL-23), whereas resistance is associated with increased allergen uptake by plasmacytoid DCs. Surprisingly, adoptive transfer of syngeneic HDM-pulsed bone marrow derived mDCs (BMDCs) to the lungs of C3H mice markedly enhanced lung IL-17A production, and rendered them susceptible to allergen-driven airway hyperresponsiveness. Characterization of these BMDCs revealed levels of antigen uptake, and Th17 promoting cytokine production similar to that observed in pulmonary mDCs from susceptible A/J mice. Collectively these data demonstrate that the lung environment present in asthma-resistant mice promotes robust pDC allergen uptake, activation, and limits Th17-skewing cytokine production responsible for driving pathologic T cell responses central to the development of allergen-induced airway hyperresponsiveness.

Endogenous Hepatocyte Growth Factor Attenuates Inflammatory Response in Glycerol-Induced Acute Kidney Injury

Background: Hepatocyte growth factor (HGF) is overexpressed after acute kidney injury (AKI). The aim of this study was to evaluate the role of endogenous HGF in the progression of the inflammatory response in glycerol-induced AKI (Gly-AKI) in rats. Methods: Renal and systemic HGF expressions were evaluated during the development of Gly-AKI. Subsequently, the blockade of endogenous HGF was analyzed in rats treated with anti-HGF antibody concomitant to glycerol injection. Apoptosis, cell infiltration and chemokine and cytokine profiles were investigated. Results: We detected an early peak of renal and plasma HGF protein expressions 3 h after glycerol injection. The pharmacological blockade of the endogenous HGF exacerbated the renal impairment, the tubular apoptosis, the renal expression of monocyte chemoattractant protein-1 and the macrophage, CD43+, CD4+ and CD8+ T lymphocytes renal infiltration. The analysis of mRNA expressions of Th1 (t-bet, TNF-α, IL-1β) and Th2 (gata-3, IL-4, IL-10) cytokines showed a Th1-polarized response in Gly-AKI rats that was aggravated with the anti-HGF treatment. Conclusion: Endogenous HGF attenuates the renal inflammatory response, leukocyte infiltration and Th1 polarization after glycerol injection. The control of cellular immune response may partly explain the protective effect of endogenous HGF in the development of Gly-AKI.

Th1 and Th2 cytokine levels in nasopharyngeal aspirates from children with human bocavirus bronchiolitis

Background Human bocavirus (hBoV) is regarded as one of the possible etiologic agents in lower respiratory tract infection and bronchial asthma exacerbation in children despite frequent co-detection with other respiratory viruses. The immunologic response in children with hBoV infection is still not clear. Objectives To investigate the profiles of T helper-1 (Th1)/T helper-2 (Th2) cytokines in children with hBoV-associated bronchiolitis. Study design This study utilized of 59 nasopharyngeal aspirates from 59 infants aged 24 months or younger, including 29 from children with hBoV-related bronchiolitis and 30 with respiratory syncytial virus (RSV)-related bronchiolitis. Eighteen infants hospitalized for elective surgeries were included as controls. Nasopharyngeal aspirates were tested simultaneously for cytokines interleukin (IL)-2, IL-4, IL-5, IL-10, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha using the Cytometric Bead Array. Results Significantly higher concentrations of IFN-gamma ( p = 0.0001), IL-2 (0.006), and IL-4 ( p = 0.0002) were observed in hBoV positive specimens than in controls. The concentration of IL-10 ( p = 0.04) and TNF-alpha ( p = 0.006) in the RSV-positive group was significantly higher than in the hBoV-positive group, while there was no difference in other cytokines concentration between the two groups. Conclusions These results showed that both of Th1 and Th2 cytokines were increased in children with hBoV-related bronchiolitis compared to normal controls, but Th2-polarized responses were not observed.

Phenotypic Switching inCryptococcus neoformansContributes to Virulence by Changing the Immunological Host Response

Cryptococcus neoformans is an encapsulated opportunistic organism that can undergo phenotypic switching. In this process, the parent smooth colony (SM) switches to a more virulent mucoid colony (MC) variant. The host responses mounted against the SM and MC variants differ, and lower tissue interleukin 10 (IL-10) levels are consistently observed in lungs of MC-infected C57BL/6 and BALB/c mice. This suggested different roles of this cytokine in SM and MC infections. The objective of this study was to compare survival rates and characterize the host responses of SM- and MC-infected IL-10-depleted (IL-10(-/-)) mice, which exhibit a Th1-polarized immune response and are considered resistant hosts. As expected, SM-infected IL-10(-/-) mice survived longer than wild-type mice, whereas MC-infected IL-10(-/-) mice did not exhibit a survival benefit. Consistent with this observation, we demonstrated marked differences in the inflammatory responses of SM- and MC-infected IL-10(-/-) and wild-type mice. This included a more Th1-polarized inflammatory response with enhanced recruitment of macrophages and natural killer and CD8 cells in MC- than in SM-infected IL-10(-/-) and wild-type mice. In contrast, both SM-infected IL-10(-/-) and wild-type mice exhibited higher recruitment of CD4 cells, consistent with enhanced survival and differences in recruitment and Th1/Th2 polarization. Lung tissue levels of IL-21, IL-6, IL-4, transforming growth factor beta, IL-12, and gamma interferon were higher in MC-infected IL-10(-/-) and wild-type mice than in SM-infected mice, whereas tumor necrosis factor alpha levels were higher in SM-infected IL-10(-/-) mice. In conclusion, the MC variant elicits an excessive inflammatory response in a Th1-polarized host environment, and therefore, the outcome is negatively affected by the absence of IL-10.

Upregulation of Cytokines Is Detected in the Placentas of Cattle Infected withNeospora caninumand Is More Marked Early in Gestation When Fetal Death Is Observed

The protozoan parasite Neospora caninum causes fetal death after experimental infection of pregnant cattle in early gestation, but the fetus survives a similar infection in late gestation. An increase in Th1-type cytokines in the placenta in response to the presence of the parasite has been implicated as a contributory factor to fetal death due to immune-mediated pathological alterations. We measured, using real-time reverse transcription-PCR and enzyme-linked immunosorbent assay, the levels of cytokines in the placentas of cattle experimentally infected with N. caninum in early and late gestation. After infection in early gestation, fetal death occurred, and the levels of mRNA of both Th1 and Th2 cytokines, including interleukin-2 (IL-2), gamma interferon (IFN-gamma), IL-12p40, tumor necrosis factor alpha (TNF-alpha), IL-18, IL-10, and IL-4, were significantly (P < 0.01) increased by up to 1,000-fold. There was extensive placental necrosis and a corresponding infiltration of CD4(+) T cells and macrophages. IFN-gamma protein expression was also highly increased, and a modest increase in transforming growth factor beta was detected. A much smaller increase in the same cytokines and IFN-gamma protein expression, with minimal placental necrosis and inflammatory infiltration, occurred after N. caninum infection in late gestation when the fetuses survived. Comparison of cytokine mRNA levels in separated maternal and fetal placental tissue that showed maternal tissue was the major source of all cytokine mRNA except for IL-10 and TNF-alpha, which were similar in both maternal and fetal tissues. These results suggest that the magnitude of the cytokine response correlates with but is not necessarily the cause of fetal death and demonstrate that a polarized Th1 response was not evident in the placentas of N. caninum-infected cattle.

The parasite Nippostrongylus brasiliensis induces multiple regulatory pathways that control increases of IL‐17 expression and associated pathology in the lung

Infection with the Nippostrongylus brasiliensis (Nb) induces a highly polarized Th2 response typically associated with elevations in IL‐4 and IL‐13. In these studies we examined the regulation of associated IL‐17 expression. Migrating Nb larvae in the lung induce considerable pathology, which is rapidly resolved. Infection induced elevated Th2 cytokine expression in the lung, and local IL‐17 gene expression and protein production were also increased. CD4+ T cells and γδT cells were identified as two major cellular sources of IL‐17. Nb infected IL‐4 knockout (KO) mice expressed significantly higher IL‐17 compared to wide type (WT) controls. Nb infection increased CD25+FoxP3+ Treg cells in the lung, which expressed elevated IL‐10 compared to Treg cells purifed from naïve mice. After anti‐CD25 depletion, Nb infection further increased local IL‐17 expression in IL‐4KO mice, suggesting that in addition to IL‐4, Treg cells modulate IL‐17 expression during parasite infection. Alternatively activated macrophages isolated Nb infected mice express dramatically increased IL‐10. In vivo IL10 blockade further increased lung IL‐17 expression. The elevated IL‐17 expression was associated with increased inflammatory cell infiltration in the lung. These data suggest that parasite infection elicits multiple independent mechanisms that together regulate local IL‐17 levels and control the severity of inflammation.

Endosomal Proteases Influence the Repertoire of MAGE-A3 Epitopes RecognizedIn vivoby CD4+ T Cells

Little is known about the repertoire of MAGE-A3 CD4(+) T-cell epitopes recognized in vivo by neoplastic patients and how antigen processing influences epitope formation. Here, we first show that MAGE-A3-specific CD4(+) T cells are present in the blood of advanced melanoma patients. MAGE-A3(111-125), MAGE-A3(191-205), and MAGE-A3(281-300) were recognized by 7, 6, and 5 of the 11 patients tested, respectively. MAGE-A3(146-160) and MAGE-A3(171-185) were also recognized in two and one cases, whereas no recognition of MAGE-A3(161-175) and MAGE-A3(243-258) was observed. Cytokines produced were mainly interleukin 5 and/or granulocyte macrophage colony-stimulating factor, suggesting impairment of productive polarized Th1 responses. Secondly, proteases inhibitors were used to modulate in vitro the recognition by CD4(+) T-cells clones of dendritic cells loaded with MAGE-A3-expressing cell lysates. We found that formation of MAGE-A3(111-125) depended on both leupeptin-sensitive and pepstatin-sensitive proteases. In contrast, we found that MAGE-A3(161-175), which was never recognized ex vivo, was formed by leupeptin but destroyed by pepstatin-sensitive proteases. Collectively, our results show that (a) anti-MAGE-A3 CD4(+) T-cell immunity develops in vivo in neoplastic patients and is focused toward immunodominant epitopes, (b) the response in advanced disease is skewed toward a Th2 type, and (c) endosomal/lysosomal proteases in dendritic cells influence the repertoire of the epitopes recognized.

IL-33, a Potent Inducer of Adaptive Immunity to Intestinal Nematodes

IL-33 (IL-1F11) binds ST2 (IL-1R4), both of which are associated with optimal CD4(+) Th2 polarization. Exogenous IL-33 drives induction of Th2-associated cytokines and associated pathological changes within the gut mucosa. Th2 polarization is also a prerequisite to expulsion of the intestinal-dwelling nematode Trichuris muris. In this study, we demonstrate that IL-33 mRNA is expressed early during parasite infection and susceptible mice can be induced to expel the parasite by a regime of exogenous IL-33 administration. IL-33 prevents an inappropriate parasite-specific Th1-polarized response and induces IL-4, IL-9, and IL-13. This redirection requires the presence of T cells and must occur at the initiation of the response to the pathogen. Interestingly, exogenous IL-33 also induced thymic stromal lymphopoietin mRNA within the infected caecum, an epithelial cell-restricted cytokine essential for the generation of Th2-driven parasite immunity. IL-33 also acts independently of T cells, altering intestinal pathology in chronically infected SCID mice, leading to an increased crypt length and intestinal epithelial cell proliferation, but reducing goblet cell hyperplasia. Thus, the ability of IL-33 to induce Th2 responses has functional relevance in the context of intestinal helminth infection, particularly during the initiation of the response.

Nasal Immunization with a Recombinant HIV gp120 and Nanoemulsion Adjuvant Produces Th1 Polarized Responses and Neutralizing Antibodies to Primary HIV Type 1 Isolates

Epidemiological and experimental data suggest that both robust neutralizing antibodies and potent cellular responses play important roles in controlling primary HIV-1 infection. In this study we have investigated the induction of systemic and mucosal immune responses to HIV gp120 monomer immunogen administered intranasally in a novel, oil-in-water nanoemulsion (NE) adjuvant. Mice and guinea pigs intranasally immunized by the application of recombinant HIV gp120 antigen mixed in NE demonstrated robust serum anti-gp120 IgG, as well as bronchial, vaginal, and serum anti-gp120 IgA in mice. The serum of these animals demonstrated antibodies that cross-reacted with heterologous serotypes of gp120 and had significant neutralizing activity against two clade-B laboratory strains of HIV (HIVBaL and HIVSF162) and five primary HIV-1 isolates. The analysis of gp120-specific CTL proliferation, INF-gamma induction, and prevalence of anti-gp120 IgG2 subclass antibodies indicated that nasal vaccination in NE also induced systemic, Th1-polarized cellular immune responses. This study suggests that NE should be evaluated as a mucosal adjuvant for multivalent HIV vaccines.

Coinfection withHeligmosomoides polygyrusFails To Establish CD8+T-Cell Immunity againstToxoplasma gondii

CD8+ T-cell immunity is important for long-term protection against Toxoplasma gondii infection. However, a Th1 cytokine environment, especially the presence of gamma interferon (IFN-), is essential for the development of primary CD8+ T-cell immunity against this obligate intracellular pathogen. Earlier studies from our laboratory have demonstrated that mice lacking optimal IFN- levels fail to develop robust CD8+ T-cell immunity against T. gondii. In the present study, induction of primary CD8+ T-cell immune response against T. gondii infection was evaluated in mice infected earlier with Heligmosomoides polygyrus, a gastrointestinal worm known to evoke a polarized Th2 response in the host. In the early stage of T. gondii infection, both CD4 and CD8+ T-cell responses against the parasite were suppressed in the dually infected mice. At the later stages, however, T. gondii-specific CD4+ T-cell immunity recovered, while CD8+ T-cell responses remained low. Unlike in mice infected with T. gondii alone, depletion of CD4+ T cells in the dually infected mice led to reactivation of chronic infection, leading to Toxoplasma-related encephalitis. Our observations strongly suggest that prior infection with a Th2 cytokine-polarizing pathogen can inhibit the development of CD8+ T-cell immune response against T. gondii, thus compromising long-term protection against a protozoan parasite. This is the first study to examine the generation of CD8+ T-cell immune response in a parasitic nematode and protozoan coinfection model that has important implications for infections where a CD8+ T-cell response is critical for host protection and reduced infection pathology.

The role of interleukin-12 in the heavy metal-elicited immunomodulation: relevance of various evaluation methods

BackgroundIncreasing evidence exists that heavy metals modulate T helper cell (Th) responses and thereby elicit various pathological manifestation. Interleukin (IL)-12, a crucial innate cytokine, was found to be regulated by such xenobiotic agents. This study aimed at testing whether IL-12 profiles may be indicative of heavy metals-induced immunomodulation.MethodsHuman immunocompetent cells, activated either by monoclonal antibodies or heat-killed Salmonella enterica, were cultured in the absence or presence of cadmium (Cd) acetate or mercuric (Hg) chloride. In vivo experiments were set up where BALB/c mice were exposed to sub-lethal doses of Cd or Hg salts for 3 or 5 weeks. Cytotoxicity was assessed by MTT-reduction assay. Modulation of cytokine profiles was evaluated by enzyme-linked immunosorbent assay (ELISA), cytometric bead-based array (CBA) and real-time polymerase chain reaction (RT-PCR); the relevance of these methods of cytokine quantification was explored.ResultsModulation of IL-12 profiles in Cd- or Hg-exposed human PBMC was dose-dependent and significantly related to IFN-γ levels as well as to the Th1- or Th2-polarized responses. Similarly, skewing the Th1/Th2 ratios in vivo correlated significantly with up- or down-regulation of IL-12 levels in both cases of investigated metals.ConclusionIt can be inferred that: (i) IL-12 profiles alone may represent a relevant indicator of heavy metal-induced immune modulation; (ii) evaluating cytokine profiles by CBA is relevant and can adequately replace other methods such as ELISA and RT-PCR in basic research as well as in immune diagnostics; and (iii) targeting IL-12 in therapeutic approaches may be promising to modify Th1/Th2-associated immune disorders.

The role of TNF‐α in Trichuris muris infection II: global enhancement of ongoing Th1 or Th2 responses

Host resistance to Trichuris muris is driven by Th2 responses. However, TNF-alpha has also been shown to play a role in protection. As TNF-alpha has a variety of actions, the exact role of TNF-alpha in immunity to T. muris is yet to be established. Here we demonstrate that although blocking TNF-alpha has been shown to abrogate resistance, rTNF-alpha treatment does not promote resistance. Further, we show that TNF-alpha functions to enhance the ongoing immune response. AKR animals that typically respond to infection with a polarized Th1 response produce greater levels of Th1 cytokines when treated with TNF-alpha and BALB/c animals that normally respond with a polarized Th2 response produce higher levels of Th2 cytokines. Crucially, blocking TNF-alpha in the strong Th2 responder strain BALB/c does not prevent expulsion of T. muris, thus supporting its role as a biological enhancer. TNF-alpha does increase transcription of both IFN-gamma and IL-13 in vitro but can also act synergistically with IL-13 in vitro to promote production of RELMbeta, which has also been shown to play a role in resistance to T. muris. Thus, this data demonstrates that TNF-alpha acts to enhance an ongoing immune response but is not necessary for a strong protective Th2 response.

Role for CD30 antigen in human T helper 2-type responses.

Human T helper 1 (Th1) cells develop preferentially during infections by intracellular parasites and trigger phagocyte-mediated host defence. In contrast, human Th2 cells are responsible for phagocyte-independent host response, and they predominate during helminthic infestations and in atopic humans in response to common environmental antigens. Polarized human Th1 and Th2 cell responses play different roles in protection, and they can promote different immunopathological reactions. Strong and persistent Th1 responses seem to be involved in organ-specific autoimmunity, contact dermatitis and some chronic non-allergic inflammatory disorders. Polarized Th2 responses favour reduced protection against the majority of infections, including HIV, and they are responsible for triggering allergic disorders in genetically predisposed hosts. Th1 and Th2 cells probably exhibit distinct surface markers; for example, Th2 cells express preferentially membrane CD30 and release the soluble form of CD30, which is a member of the tumour necrosis factor receptor superfamily. CD30-mediated signalling promotes the in vitro development of Th2-like cells. The expression of CD30 in HIV-infected T cells results in enhanced HIV replication, suggesting the existence of complex links among CD30 expression, production of Th2-type cytokines and immunopathogenesis of HIV infection.

Reversal of polarized T helper 1 and T helper 2 cell populations in murine leishmaniasis.

T helper 1 (Th1) and Th2 cells are the major subsets of fully differentiated CD4+ T cells in the mouse. The spectrum of cytokines characteristic of each subset determines the distinctive regulatory and effector functions mediated by each subset. We have used the murine model of Leishmania major infection to study the question of whether highly polarized populations of normal T cells are as stable in their cytokine phenotype as Th clones or whether the phenotype can be altered with regulatory cytokines. Interleukin 4 (IL-4) appears to be a key cytokine for Th2 responses as it is necessary for both the initial differentiation of Th responses to L. major and the stability of ongoing responses. Furthermore, IL-4 is capable of converting highly polarized Th1 responses to Th2 responses either in vitro or when adoptively transferred to severe combined immunodeficiency mice.

The Role of B Cells in the Development of CD4 Effector T Cells during a Polarized Th2 Immune Response

Previous studies have suggested that B cells promote Th2 cell development by inhibiting Th1 cell differentiation. To examine whether B cells are directly required for the development of IL-4-producing T cells in the lymph node during a highly polarized Th2 response, B cell-deficient and wild-type mice were inoculated with the nematode parasite, Nippostrongylus brasiliensis. On day 7, in the absence of increased IFN-gamma, IL-4 protein and gene expression from CD4 T cells in the draining lymph nodes were markedly reduced in B cell-deficient mice and could not be restored by multiple immunizations. Using a DO11.10 T cell adoptive transfer system, OVA-specific T cell IL-4 production and cell cycle progression, but not cell surface expression of early activation markers, were impaired in B cell-deficient recipient mice following immunization with N. brasiliensis plus OVA. Laser capture microdissection and immunofluorescent staining showed that pronounced IL-4 mRNA and protein secretion by donor DO11.10 T cells first occurred in the T cell:B cell zone of the lymph node shortly after inoculation of IL-4-/- recipients, suggesting that this microenvironment is critical for initial Th2 cell development. Reconstitution of B cell-deficient mice with wild-type naive B cells, or IL-4-/- B cells, substantially restored Ag-specific T cell IL-4 production. However, reconstitution with B7-1/B7-2-deficient B cells failed to rescue the IL-4-producing DO11.10 T cells. These results suggest that B cells, expressing B7 costimulatory molecules, are required in the absence of an underlying IFN-gamma-mediated response for the development of a polarized primary Ag-specific Th2 response in vivo.

Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes

Asthma is a chronic airway inflammatory disease that encompasses three cardinal processes: T helper (Th) cell type 2 (Th2)-polarized inflammation, bronchial hyperreactivity, and airway wall remodeling. However, the link between the immune-inflammatory phenotype and the structural-functional phenotype remains to be fully defined. The objective of these studies was to evaluate the relationship between the immunologic nature of chronic airway inflammation and the development of abnormal airway structure and function in a mouse model of chronic asthma. Using IL-4-competent and IL-4-deficient mice, we created divergent immune-inflammatory responses to chronic aeroallergen challenge. Immune-inflammatory, structural, and physiological parameters of chronic allergic airway disease were evaluated in both strains of mice. Although both strains developed airway inflammation, the profiles of the immune-inflammatory responses were markedly different: IL-4-competent mice elicited a Th2-polarized response and IL-4-deficient mice developed a Th1-polarized response. Importantly, this chronic Th1-polarized immune response was not associated with airway remodeling or bronchial hyperresponsiveness. Transient reconstitution of IL-4 in IL-4-deficient mice via an airway gene transfer approach led to partial Th2 repolarization and increased bronchial hyperresponsiveness, along with full reconstitution of airway remodeling. These data show that distinct structural-functional phenotypes associated with chronic airway inflammation are strictly dependent on the nature of the immune-inflammatory response.