Biomedical subjects

W C Brown

Publications and source records attributed to W C Brown.

At least 37 records · Page 2Linked to original sources

PubMed2000

An in vivo model to investigate lymphocyte-mediated immunity during acute hemoparasitic infections. Use of a monoclonal antibody to selectively deplete CD4+ T lymphocytes from thymectomized calves.

Thymectomized calves were selectively depleted of CD4+ T lymphocytes with a monoclonal antibody (mAb) specific for the bovine CD4 monomer (ILA-11). Calves were treated with high loading doses of ILA-11 during the first week of the study then treated with subsequent lower maintenance doses. Depletion of CD4+ T lymphocytes was assessed weekly by flow cytometric analysis of PBMC and mononuclear cells from lymph node and spleen biopsies. Treatment with high doses of ILA-11 resulted in rapid and marked depletion of CD4+ T lymphocytes from the peripheral blood, peripheral lymph nodes, and spleen. Although CD4+ T lymphocytes slowly returned to the peripheral blood, peripheral lymph nodes, and spleen by day 21 post-treatment, the numbers of CD4+ T lymphocytes in depleted calves remained below pre-depletion levels for the duration of the study. CD4+ T lymphocytes failed to be effectively depleted from a non-thymectomized calf treated with the mAb ILA-11. Development of a T lymphocyte depletion model in thymectomized calves will permit testing of the hypothesis that CD4+ T lymphocytes and IFN-gamma are required in cattle for control of acute anaplasmosis. In subsequent planned studies, thymectomized calves depleted of CD4+ T lymphocytes will be experimentally infected with A. marginale and parameters of disease compared between depleted and non-depleted calves.

Anaplasmosis↗

PubMed2000

Interleukin-12 as an adjuvant promotes immunoglobulin G and type 1 cytokine recall responses to major surface protein 2 of the ehrlichial pathogen Anaplasma marginale.

Anaplasma marginale is a tick-transmitted pathogen of cattle closely related to the human ehrlichiae, Ehrlichia chaffeensis and the agent of human granulocytic ehrlichiosis (HGE). These pathogens have in common a structurally conserved outer membrane protein (OMP) designated the major surface protein 2 (MSP-2) in A. marginale and HGE and OMP-1 in E. chaffeensis. Protective immunity against ehrlichial pathogens is believed to require induction of gamma interferon (IFN-gamma) and opsonizing immunoglobulin (Ig) subclasses directed against OMP epitopes that, in concert, activate macrophages for phagocytosis and killing. Because interleukin-12 (IL-12) acts as an adjuvant for protein immunization to induce IFN-gamma and protective immunity against intracellular pathogens, we hypothesized that as an adjuvant with MSP-2, IL-12 would augment type 1 recall responses to A. marginale. IL-12 was coadsorbed with MSP-2 to alum and shown to significantly enhance IFN-gamma production by lymph node cells (LNC) and LNC-derived CD4(+) T-cell lines from immunized calves following recall stimulation with A. marginale. LNC proliferation and IL-2 production were also enhanced in IL-12-treated calves. Elevated recall proliferative responses by peripheral blood mononuclear cells were still evident 9 months after immunization. Serum IgG levels were consistently increased in IL-12 immunized calves, predominantly due to higher IgG1 responses. The results support the use of IL-12 coadsorbed with OMP of ehrlichial pathogens in alum to amplify both antibody and type-1 cytokine responses important for protective immunity.

Adjuvants, Immunologic↗

PubMed2000

Characterization of allelic variation in the Babesia bovis merozoite surface antigen 1 (MSA-1) locus and identification of a cross-reactive inhibition-sensitive MSA-1 epitope.

The Babesia bovis merozoite surface antigen 1 (MSA-1), a member of the variable merozoite surface antigen (VMSA) family, is an immunodominant glycoprotein which elicits antibodies that inhibit erythrocyte invasion. While antigenic polymorphism is a general feature of vmsa genes, the molecular basis and extent of msa-1 sequence polymorphism have not been well characterized. In this study we defined the msa-1 locus in the biologically cloned Mexico Mo7 strain of B. bovis and identified the sequence differences between MSA-1 antigenically dissimilar strains. We then determined whether sequences conserved between distinct msa-1 alleles would induce cross-reactive CD4(+) T lymphocytes or inhibitory antibodies. The msa-1 locus in Mo7 contains a single msa-1 gene flanked by transcribed genes with no sequence homology to members of the VMSA gene family. Argentina B. bovis strains R1A and S2P have msa-1 genes with amino acid sequences that are 98.8% identical to each other, and antibodies against S2P MSA-1 cross-react with native R1A MSA-1. In contrast, identity between the Argentina and Mexico Mo7 msa-1 alleles is only 52%, with no continuous stretch of identity longer than 16 amino acids. Despite limited sequence conservation, antibodies against R1A MSA-1 were able to inhibit invasion of erythrocytes by Mo7 merozoites. The results indicate that inhibition-sensitive epitopes are conserved despite significant sequence divergence between Mexico and Argentina strain alleles and support a conserved functional role for polymorphic MSA-1 in erythrocyte invasion.

Alleles↗

PubMed2000

Identification of Cowdria ruminantium antigens that stimulate proliferation of lymphocytes from cattle immunized by infection and treatment or with inactivated organisms.

Cowdria ruminantium is an obligate intracellular pathogen that causes heartwater in ruminants. Several findings suggest that T cells play an important role in protection against the disease. In order to identify which proteins are involved in T-cell immunity, C. ruminantium proteins were fractionated by continuous-flow electrophoresis and tested for their ability to stimulate lymphocyte proliferation in vitro. C. ruminantium-infected endothelial cell lysates were fractionated at between 11 and 38 kDa and 50 and 168 kDa on 15 and 7% acrylamide gels, respectively. In an attempt to stimulate the natural infective process, peripheral blood mononuclear cells (PBMC) were obtained from two cattle rendered immune by infection and treatment and assayed in proliferation assays with fractionated proteins. In a parallel study, four cattle were immunized with inactivated C. ruminantium to determine whether their lymphocytes also responded to fractionated proteins. Proliferation assays after immunization by infection and treatment detected no C. ruminantium-specific proliferation in vitro after one vaccination. Proliferation was observed, however, between 1 and 4 weeks after challenge. This was followed by a period of no detectable response, after which the response reappeared. PBMC from animals immunized with inactivated organisms proliferated specifically in response to antigen soon after the first immunization. Only C. ruminantium proteins with low molecular masses of 11, 12, 14 to 17, and 19 to 23 kDa induced proliferative responses by lymphocytes from all six animals. These protein fractions may have potential as vaccine antigens.

Animals↗

PubMed2000

Expression of polymorphic msp1beta genes during acute anaplasma Marginale rickettsemia.

Immunization of cattle with native MSP1 induces protection against Anaplasma marginale. The native immunogen is composed of a single MSP1a protein and multiple, undefined MSP1b polypeptides. In addition to the originally sequenced gene, designated msp1beta(F1), we identified three complete msp1beta genes in the Florida strain: msp1beta(F2), msp1beta(F3), and msp1beta(F4). Each of these polymorphic genes encodes a structurally unique MSP1b protein, and unique transcripts can be identified during acute A. marginale rickettsemia. The structural polymorphism is clustered in discrete variable regions, and each MSP1b protein results from a unique mosaic of five variable regions. Although each of the MSP1b proteins in the Florida strain contains epitopes recognized by serum antibody induced by protective immunization with the native MSP1 complex, the variable regions also include epitopes expressed by some but not all of the MSP1b proteins. These data support testing recombinant vaccines composed of the multiple antigenically and structurally unique MSP1b proteins combined with MSP1a in order to mimic the efficacy of native MSP1 immunization.

Amino Acid Sequence↗

PubMed2000

Babesia bovis-stimulated macrophages express interleukin-1beta, interleukin-12, tumor necrosis factor alpha, and nitric oxide and inhibit parasite replication in vitro.

The tick-transmitted hemoparasite Babesia bovis causes an acute infection that results in persistence and immunity against challenge infection in cattle that control the initial parasitemia. Resolution of acute infection with this protozoal pathogen is believed to be dependent on products of activated macrophages (Mphi), including inflammatory cytokines and nitric oxide (NO) and its derivatives. B. bovis stimulates inducible nitric oxide synthase (iNOS) and production of NO in bovine Mphi, and chemical donors of NO inhibit the growth of B. bovis in vitro. However, the induction of inflammatory cytokines in Mphi by babesial parasites has not been described, and the antiparasitic activity of NO produced by B. bovis-stimulated Mphi has not been definitively demonstrated. We report that monocyte-derived Mphi activated by B. bovis expressed enhanced levels of inflammatory cytokines interleukin-1beta (IL-1beta), IL-12, and tumor necrosis factor alpha that are important for stimulating innate and acquired immunity against protozoal pathogens. Furthermore, a lipid fraction of B. bovis-infected erythrocytes stimulated iNOS expression and NO production by Mphi. Cocultures of Mphi and B. bovis-infected erythrocytes either in contact or physically separated resulted in reduced parasite viability. However, NO produced by bovine Mphi in response to B. bovis-infected erythrocytes was only partially responsible for parasite growth inhibition, suggesting that additional factors contribute to the inhibition of B. bovis replication. These findings demonstrate that B. bovis induces an innate immune response that is capable of controlling parasite replication and that could potentially result in host survival and parasite persistence.

Animals↗

PubMed1999

Functional implications for signaling via the IL4R/IL13R complex on bovine cells.

IL-4 and IL-13 share a wide range of activities on monocytes, epithelial cells and B cells and thus play an important role in host defense. Many of these activities are not conserved among species as human, but not murine, B cells are thought to be responsive to IL-13. We previously demonstrated that human IL-13 is highly conserved at the nucleic acid level with a candidate bovine IL-13 cDNA homologue. Moreover, recombinant human IL-13 stimulates Ig secretion by appropriately activated bovine B cells. These studies have been extended to examining Ig class switching at both the protein and mRNA levels in addition to examining other markers of cellular activation. Our results suggest that IL-13 influences B cell differentiation by enhancing IgM, IgG1, and IgE production. IL-13 stimulation alone increases MHC class II expression and progression through cell cycle, although at lower levels in comparison to rboIL-4. The biology of the receptors for IL-4 and IL-13 is complex and raises several key questions with regard to IL-4-dependent and -independent mechanisms of host immunomodulation. Recent studies suggest that at least four chains are involved. These include the p140 IL-4 binding chain (IL-4Ralpha), the common gamma chain (gammac chain), IL-13 receptor alpha- chain (IL-13Ralpha-1) and the IL-13 receptor alpha-2 chain (IL-13Ralpha-2). We have recently cloned cDNAs for the bovine homologues of the IL-13Ralpha-1 and IL-4Ralpha chains and evaluated mRNA expression for a variety of cell types following stimulation. The expression patterns and their implications for receptor chain utilization in signaling via these key TH2 signature cytokines will be discussed.

Amino Acid Sequence↗

PubMed1999

Modulation of host immune responses by protozoal DNA.

The pathology caused by acute Babesia bovis infection is similar to that seen in severe human malaria caused by Plasmodium falciparum infection, which is related to dysregulated production of inflammatory cytokines and nitric oxide (NO). We have observed induction of NO, inducible nitric oxide synthase (iNOS) and inflammatory cytokines in macrophages by B. bovis. Furthermore, proliferation of lymphocytes from individuals never exposed to certain protozoal pathogens can be induced by crude protozoal parasite extracts. We have repeatedly observed stimulation of naive PBMC from cattle to antigenic extracts of Babesia bovis. Based on recent studies demonstrating the mitogenicity of bacterial and other non-vertebrate DNAs for murine B cells and macrophages, the mitogenic properties of B. bovis DNA were examined. B. bovis and E. coli DNAs induced proliferation of PBMC and purified B cells from non-exposed cattle. Stimulatory activity was reduced by DNase treatment and methylation with CpG methylase, indicating the presence of stimulatory non-methylated CpG motifs in the B. bovis genome. B. bovis and E. coli DNAs enhanced IgG secretion by cultured B cells, stimulating IgG1 and more strongly, IgG2. Several hexameric CpG immunostimulatory sequences (ISS) active for murine B cells were identified in an 11 kb fragment of B. bovis DNA. An oligodeoxyribonucleotide containing one of these (AACGTT), located in the rhoptry associated protein-1 (rap-1) open reading frame, stimulated B cell proliferation. These studies identify a potential mechanism by which protozoal parasites may modulate host immune responses, leading to consequences such as hypergammaglobulinemia and splenomegaly. These results also support the use of ISS as vaccine adjuvants to enhance Type 1 immune responses in cattle.

Animals↗

PubMed1999

Bovine T cell responses to recombinant thioredoxin of Fasciola hepatica.

Fasciolosis is an economically significant disease of ruminants, caused by infection with the digenetic trematodes, Fasciola hepatica and F. gigantica. Some vaccination trials using irradiated metacercariae or isolated proteins have been shown to afford significant protection. However, the mechanisms of specific immunity against this pathogen have not been elucidated. We have identified thioredoxin, a tegument antigen of F. hepatica, among several proteins that are common to both the juvenile and adult fluke within the mammalian host and have undertaken studies to characterize bovine T cell responses to recombinant thioredoxin protein (FH 2020). Peripheral blood mononuclear cells from immune cattle proliferated specifically to crude F. hepatica antigenic extract but not to FH 2020. However, after repeated stimulation of lymphocytes by alternating crude extract and FH 2020, FH 2020-specific proliferation by T cell lines was observed. T cell clones were subsequently generated and found to respond specifically but weakly to both crude antigen and FH 2020. Thioredoxin appears to be only weakly antigenic for bovine T cells and is, therefore, an unpromising candidate for inducing resistance to F. hepatica.

Animals↗

PubMed1999

Development and in vitro characterization of recombinant vaccinia viruses expressing bovine leukemia virus gp51 in combination with bovine IL4 or IL12.

Type 1 and type 2 immune responses are modulated by IL12 or IL4, respectively, at the time of lymphocyte priming. Importantly, type 1 responses have been associated with resistance to retroviral infection in mice, humans, and ruminants. Specifically, vaccination of sheep with vaccinia virus expressing bovine leukemia virus (BLV) gp51 resulted in protective immunity with the characteristics of a type 1 response, whereas vaccination of cattle resulted in a non-protective type 2 response. In order to test the hypothesis that cattle inoculated with BLV gp51 and IL12 will respond with a type 1 response, a recombinant vaccinia virus expressing BLV gp51 together with bovine IL12 was developed and characterized in vitro. For induction of type 2 responses a recombinant vaccinia virus expressing gp51 with bovine IL4 was similarly constructed and characterized. In this study recombinant cassettes were developed containing either the BLVenv gene alone or in combination with bovine IL4 or the two genes, p35 and p40, encoding bovine IL12. Correct alignment with p7.5 or p11 vaccinia promoters and orientation was confirmed by complete sequencing. Recombinant vaccinia viruses were generated by homologous recombination, selected based on large plaque formation due to reconstitution of the vp37 gene, and structurally confirmed by Southern blotting. Transcription of recombinant BLVenv, bovine IL4, p35 and p40 was demonstrated by RT-PCR. Expression of BLVenv gp51 protein and bovine IL4 was shown by immunofluorescence and immunoblotting. Biologically active bovine IL4 expressed by vaccinia virus stimulated lymphoblast proliferation, B lymphocyte proliferation in the presence of CD40L, and inhibited IFN gamma secretion from PHA activated PBMC in a dose dependent fashion. Finally, bovine IL12 expression and biological function was confirmed by dose dependent induction of IFN gamma secretion by PHA activated PBMC and the moderate enhancement of lymphoblast proliferation. In conclusion, bovine IL12 and IL4 expressed by recombinant vaccinia virus in vitro clearly exhibited type 1-type 2 modulating properties.

Amino Acid Sequence↗

PubMed1999

Differential effects of type I IFNs on the growth of WC1- CD8+ gamma delta T cells and WC1+ CD8- gamma delta T cells in vitro.

Type I IFNs have a broad array of immunoregulatory functions that include up-regulation of type 1 immune responses through enhancing differentiation and activation of CD8+ T cells and CD4+ Th1 cells. Ovine trophoblast IFN-tau is a recently described type I IFN with the potential for therapeutic use, based on its potent antiviral activity yet low toxicity. Studies were designed to determine the immunoregulatory effects of IFN-tau on Ag-stimulated T cells, and a novel effect of type I IFNs on gammadelta T cells was observed. In cultures of parasite Ag-stimulated bovine T cells that contained a mixture of alphabeta and gammadelta T cells, both IFN-tau and IFN-alpha suppressed the expansion of WC1+ CD2- CD6- CD8- gammadelta T cells, yet stimulated the growth of WC1- CD2+ CD6+ CD8+ gammadelta T cells and CD8+ alphabeta T cells. The CD8+ gammadelta T cell subset expressed high levels of the IL-2R alpha-chain. Furthermore, we showed that type I IFN enhanced IL-2 production by these Ag-stimulated T cell lines. In short term cultures of PBMC, IL-2 stimulated an expansion of WC1- CD6+ CD8+ gammadelta T cells, which was significantly increased by IFN-tau, even though IFN-tau alone did not support cell survival. These studies demonstrate for the first time that type I IFNs differentially modulate the proliferation of different subsets of gammadelta T cells, which appears to act in part via IL-2.

Animals↗

PubMed1999

Babesia bovis: common protein fractions recognized by oligoclonal B. bovis-specific CD4+ T cell lines from genetically diverse cattle.

CD4+ helper T cells are believed to be important for inducing protective immunity against Babesia bovis through the production of cytokines, including IFN-gamma, that will provide help to B lymphocytes for IgG production and activate macrophages to become parasiticidal. To provide maximum protection in an outbred population, an effective vaccine against B. bovis should contain antigens that would elicit an IFN-gamma response and would be recognized by cattle with diverse genetic backgrounds. To identify potentially protective "universal" T helper (Th) cell antigens, fractions of homogenized B. bovis merozoites were tested for the ability to stimulate proliferation of oligoclonal CD4+, IFN-gamma-producing T cell lines derived from four immune animals previously shown to differ in major histocompatibility complex class II expression. Homogenized B. bovis merozoites were separated by denaturing continuous flow electrophoresis (CFE) on 15, 10, and 7.5% polyacrylamide gels into fractions containing proteins ranging from <14.5 to approximately 95 kDa. Eighteen of 280 CFE fractions elicited anamnestic proliferative responses in all T cell lines tested. Nine of these cross-stimulatory fractions contained proteins of <14.5 to 24.5 kDa, and the remaining ones contained proteins with estimated molecular weights of 30, 31.5, 44.5, 49, 49.5, 54, 62, 72, and 82 kDa. Immunoblot analysis showed that four cross-stimulatory fractions contained a predicted known B. bovis antigen of similar molecular size. Previous studies had demonstrated that fractionated merozoite proteins stimulatory for CD4+ Th cell clones had apparent molecular weights similar to those present in 7 of the 18 stimulatory fractions. In the present study, two Th cell clones responded to cross-stimulatory CFE fractions, underscoring the potential to use both oligoclonal and monoclonal Th cell lines to identify commonly recognized polypeptides as potential vaccine antigens.

Animals↗

PubMed1999

Molecular basis for vaccine development against the ehrlichial pathogen Anaplasma marginale.

Anaplasma marginale is a tick-transmitted ehrlichial pathogen causing severe morbidity and mortality in livestock on six continents. Development of safe effective vaccines would be greatly facilitated by identification of the protective immune mechanisms and by understanding how the pathogen evades immune effectors to establish persistent infection. In this article, Guy Palmer and colleagues review recent progress in identifying how defined epitopes induce protective immunity and the role of antigenic variation in these epitopes as a mechanism of persistence.

Anaplasma↗

PubMed1999

Designing blood-stage vaccines against Babesia bovis and B. bigemina.

The tick-transmitted apicomplexan parasites Babesia bovis and B. bigemina cause significant disease in cattle in many tropical and temperate areas of the world. These parasites present a challenge for vaccine development, and yet provide a system for studying the pathogenesis, mechanisms of protective immunity and regulation of host immune responses associated with intraerythrocytic protozoan parasites in a non-rodent species. In this article, Wendy Brown and Guy Palmer review strategies for identifying candidate vaccine antigens of B. bovis and B. bigemina and for priming immune responses to evoke strain crossprotective immunity.

Animals↗

PubMed1999

Immunoregulatory roles of interleukin-13 in cattle.

Interleukin-13 (IL-13) is produced predominantly by helper T lymphocytes of the Th2 phenotype and mediates its effects on several immune cells, including B lymphocytes and macrophages, stimulating their proliferation, differentiation, and effector functions. IL-13 activates human B cells but has no detectable activity on murine B lymphocytes, suggesting that the activity of IL-13 varies among species. Our studies show that IL-13 enhances proliferation and differentiation of bovine B cells and upregulates cell surface major histocompatibility complex (MHC) class II expression. We examined mRNA expression of the putative signaling component of the bovine IL-13Ralpha1 homolog in several peripheral blood populations. After stimulation with calcium ionophore and phorbol ester, IL-13Ralpha1 mRNA levels appeared to be downmodulated in T cells, upregulated in macrophages and B cells, and unchanged in neutrophils. Together, these studies begin to provide insight into the relative importance of IL-13 in immunoregulation in cattle.

Adjuvants, Immunologic↗

PubMed1999

Cloning of a cDNA encoding bovine interleukin-18 and analysis of IL-18 expression in macrophages and its IFN-gamma-inducing activity.

Interleukin-18 (IL-18) is a recently described cytokine that enhances interferon-gamma (IFN-gamma) production, either independently or synergistically with IL-12. These properties identify IL-18 as an immunoregulatory cytokine that may be pivotal in host defense against intracellular pathogens. We have isolated and sequenced a cDNA encoding bovine IL-18. The open reading frame (ORF) is 582 bp in length, encoding a predicted 192 amino acid (aa) precursor protein. Multiple sequence alignment demonstrated that bovine IL-18 has 65% and 78% identity with the predicted amino acid sequences of murine and human IL-18, respectively. IL-18 mRNA was constitutively present in bovine peripheral blood monocyte-derived macrophages (MDM), with no upregulation on stimulation with lipopolysaccharide (LPS). IL-18 transcripts were weakly detected in B lymphocytes but inducible in the B cell line BL-3. Human recombinant IL-18 (rHuIL-18) induced IFN-gamma production by PHA-stimulated peripheral blood mononuclear cells (PBMC), which was potentiated by rHuIL-12. Further, rHuIL-12 and rHuIL-18 enhanced proliferation of untreated PBMC. Antigen-specific T cell lines demonstrated IL-18-dependent enhancement of IFN-gamma production, indicating that bovine T cells are one of the leukocyte subsets that respond to IL-18. Analysis of IL-18 expression and its ability to induce IFN-gamma production by bovine lymphocytes are important considerations for understanding mechanisms of protective immunity and designing vaccines for intracellular pathogens.

Amino Acid Sequence↗

PubMed1999

Comparative effects of interleukin-12 and interleukin-4 on cytokine responses by antigen-stimulated memory CD4+ T cells of cattle: IL-12 enhances IFN-gamma production, whereas IL-4 has marginal effects on cytokine expression.

Interleukin-12 (IL-12) and IL-4 are important immunoregulatory cytokines that determine the fate of naive T cells during antigen priming in mice and also influence cytokine synthesis by differentiated murine and human T cells. The roles of these cytokines in regulating the differentiation and effector function of bovine T cells are less well studied. We investigated the ability of human IL-12 and bovine IL-4 to modify cytokine expression by antigen-stimulated T cells from cattle immune to the protozoal parasites Babesia bovis and Babesia bigemina or reactive with Mycobacterium bovis purified protein derivative. Peripheral blood mononuclear cells (PBMC) were cultured with specific antigen and IL-4 or IL-12 for 1 week. Then viable lymphoblasts consisting of predominantly CD4+ T cells were restimulated with antigen and antigen-presenting cells (APC) with or without cytokine. Cell lines were cultured for several weeks, and following restimulation with antigen and APC in the absence of exogenous cytokine, the cell lines were analyzed for proliferation, interferon-gamma (IFN-gamma) production, and expression of IL-2, IL4-, IL-10, or IFN-gamma transcript levels using a quantitative competitive RT-PCR. IL-12 and IL-4 had no effect on the composition of CD4, CD8, or gammadelta T cells in the cell lines or on the level of antigen-induced proliferation. IL-12 stimulated enhanced levels of IFN-gamma protein and transcript expression in all cell lines, with no consistent effects on IL-2 or IL-4 expression. In two B. bovis-specific cell lines, IL-12 suppressed IL-10 expression. IL-4 had no consistent effect on expression of any cytokine. These results indicate the use of IL-12 as an adjuvant to enhance type 1 cytokine responses in cattle during antigen priming.

Animals↗

PubMed1999

Upregulation of interleukin-4 and IFN-gamma expression by IFN-tau, a member of the type I IFN family.

Trophoblast interferon-tau (IFN-tau) is a new member of the type I IFN family that is produced in large quantities by the ruminant conceptus. Like other type I IFN, IFN-tau inhibits viral replication and activates natural killer (NK)-mediated cytotoxicity. In mice and humans, type I IFN enhances type 1 T helper (Th) cell responses, but the effects of type I IFN, including IFN-tau, on cytokine expression by bovine Th cells have not been described. The present study determined the effects of IFN-tau on interleukin-4 (IL-4), IFN-gamma, and IL-10 expression by antigen-specific, CD4+ T cell lines derived from cattle immune to either Babesia bovis, Babesia bigemina rhoptry-associated protein-1, or Anaplasma marginale. IFN-tau upregulated IFN-gamma secretion and steady-state levels of IFN-gamma and IL-4 mRNA by cell lines cultured for 3-6 weeks. In contrast, the steady-state levels of IL-10 mRNA were either not changed or inhibited at these times. Similar effects were obtained with human IFN-alpha. Comparison of the quantities of IFN-gamma, IL-4, and IL-10 transcripts in IFN-tau-treated or IFN-alpha-treated cultures revealed that even though IFN-gamma was the predominant cytokine expressed by all T cell lines, both IFN-gamma and IL-4 steady-state transcript levels were upregulated by a comparable degree. Thus, these studies demonstrate that IFN-tau is an immunomodulatory cytokine that promotes enhanced IL-4 and IFN-gamma responses by effector T cells but not, strictly speaking, Thl-biased responses in cattle. These results indicate the potential use of this cytokine as an adjuvant in ruminants to boost cell-mediated immune responses.

Animals↗