Central role of endogenous gamma interferon in protective immunity against blood-stage Plasmodium chabaudi AS infection

The role of endogenous gamma interferon (IFN-gamma) in protective immunity against blood-stage Plasmodium chabaudi AS malaria was studied using IFN-gamma gene knockout (GKO) and wild-type (WT) C57BL/6 mice. Following infection with 10(6) parasitized erythrocytes, GKO mice developed significantly higher parasitemia during acute infection than WT mice and had severe mortality. In infected GKO mice, production of interleukin 12 (IL-12) p70 and tumor necrosis factor alpha in vivo and IL-12 p70 in vitro by splenic macrophages was significantly reduced compared to that in WT mice and the enhanced nitric oxide (NO) production observed in infected WT mice was completely absent. WT and GKO mice had comparable numbers of total nucleated spleen cells and B220(+) and Mac-1(+) spleen cells both before and after infection. Infected WT mice, however, had significantly more F4/80(+), NK1.1(+), and F4/80(+)Ia(+) spleen cells than infected GKO mice; male WT had more CD3(+) cells than male GKO mice. In comparison with those from WT mice, splenocytes from infected GKO mice had significantly higher proliferation in vitro in response to parasite antigen or concanavalin A stimulation and produced significantly higher levels of IL-10 in response to parasite antigen. Infected WT mice produced more parasite-specific immunoglobulin M (IgM), IgG2a, and IgG3 and less IgG1 than GKO mice. Significant gender differences in both GKO and WT mice in peak parasitemia levels, mortality, phenotypes of spleen cells, and proliferation of and cytokine production by splenocytes in vitro were apparent during infection. These results thus provide unequivocal evidence for the central role of endogenous IFN-gamma in the development of protective immunity against blood-stage P. chabaudi AS.     

Role of endogenous gamma interferon in host response to infection with blood-stage Plasmodium chabaudi AS.

The role of gamma interferon (IFN-gamma), a pluripotent lymphokine capable of activating macrophages, in acquired immunity to blood-stage malaria was investigated. C57BL-derived, lipopolysaccharide-resistant C57BL/10ScN mice, which were found to be resistant to intraperitoneal (i.p.) infection with 10(6) Plasmodium chabaudi AS parasitized erythrocytes, were treated with monoclonal anti-IFN-gamma antibody (MAb). Two MAbs were used: R4-6A2, a rat anti-mouse, neutralizing immunoglobulin G1, which was prepared against natural murine IFN-gamma, and DB-1, a murine anti-rat immunoglobulin G1 prepared against recombinant rat IFN-gamma, which can neutralize the murine molecule as well as the rat molecule. C57BL/10ScNH mice were injected i.p. with 200 micrograms of R4-6A2 1 day before infection and every 3 days through day 21. Control mice were treated with normal rat serum. In separate experiments, DB-1 (1.0 mg per week for 4 weeks) was administered i.p. to C57BL/10ScNH mice beginning on the day of infection; control mice were untreated. Control and MAb-treated mice were infected i.p. with 10(6) P. chabaudi AS parasitized erythrocytes, and the course and outcome of infection were determined. Control mice exhibited a course of infection that was characterized by a peak parasitemia between 30 and 40% parasitized erythrocytes and elimination of the parasite by 4 weeks. MAb-treated mice exhibited a significantly greater parasitemia 1 to 2 days before the peak parasitemia as well as a significantly greater peak parasitemia but also completely cleared the infection by 4 weeks. Thus, these results suggest that treatment with anti-IFN-gamma MAb impairs but does not completely abrogate host resistance to P. chabaudi AS. We also examined the kinetics of IFN-gamma production by spleen cells cultured in vitro with malaria antigen or concanavalin A. Spleen cells were recovered from individual C57BL/6 mice at various times after i.p. infection with 10(6) P. chabaudi AS parasitized erythrocytes. The amount of IFN-gamma produced was quantitated by enzyme-linked immunosorbent assay. In each case, the peak of IFN-gamma production occurred just before the peak parasitemia, followed by a decrease to little or no IFN-gamma production through 42 days postinfection. There was thus a parallel between the kinetics of production of IFN-gamma in vitro by spleen cells from infected animals and the requirement in vivo for the endogenous molecule just before and at the time of peak parasitemia. In conclusion, these results suggest that IFN-gamma-dependent and -independent mechanisms contribute to host resistance to P. chabaudi AS.     

Gamma interferon production by hepatic NK T cells during Escherichia coli infection is resistant to the inhibitory effects of oxidative stress

The reductive-oxidative status of tissues regulates the expression of many inflammatory genes that are induced during gram-negative bacterial infections. The cytokine gamma interferon (IFN-gamma) is a potent stimulus for host inflammatory gene expression, and oxidative stress has been shown to inhibit its production in mice challenged with Escherichia coli bacteria. The objective of the present study was to characterize the cells that produced IFN-gamma in a mouse bacterial peritonitis model and determine the effects of oxidative stress on their activation. The liver contained large numbers of IFN-gamma-expressing lymphocytes following challenge with viable E. coli bacteria. The surface phenotypes of IFN-gamma-expressing hepatic lymphocytes were those of natural killer (NK) cells (NK1.1(+) CD3(-)), conventional T cells (NK1.1(-) CD3(+)), and NK T cells (NK1.1(+) CD3(+)). Treating mice with diethyl maleate to deplete tissue thiols significantly impaired IFN-gamma production by NK cells, conventional T cells, and CD1d-restricted NK T cells in response to E. coli challenge. However, IFN-gamma expression by a subset of NK T cells, which did not bind alpha-galactosylceramide-CD1d tetramers, was resistant to the inhibitory effects of tissue oxidative stress. Stress-resistant IFN-gamma-expressing cells were also predominantly CD8(+) and bore gamma delta T-cell antigen receptors. The residual IFN-gamma response by NK T cells may explain previous reports of hepatic gene expression following gram-negative bacterial challenge in thiol-depleted mice. The finding also demonstrates that innate immune cells differ significantly in their responses to altered tissue redox status.     

Abnormal interferon production and NK cell responses to interferon in children with Down's syndrome

Peripheral blood mononuclear leucocytes (PBL) of 11 children with Down's syndrome (DS, trisomy 21) and 13 healthy control children were examined for interferon (IFN) producing ability and for proliferation after in vitro exposure to various stimulants. Natural killer (NK) activity and in vitro sensitivity to IFN-α were also studied. Cells from DS patients showed a higher IFN production than normal cells, after stimulation with the IFN-γ inducers, concanavalin A and Lens culinaris lectin (LCL). Sendai Virus and β-haemolytic Streptococci group G also induced a higher IFN-α production in DS cells compared to normal PBL. Stimulation of DS PBL with Staphylococcus aureus Cowan I, which is an inducer of acid labile IFN-α in null lymphocytes, caused less IFN production in DS PBL than in normal cells. Basal NK activity was similar in DS and control PBL, but the NK activity of DS cells was more enhanced than in control cells by equivalent IFN concentrations in vitro, i.e. DS cells were more sensitive to IFN. There was no difference between DS children with and without a history of increased incidence of severe bacterial infections in any of the analysed parameters.     

Host defenses in murine malaria: analysis of the mechanisms of immunity to Plasmodium berghei generated in response to immunization with formalin-killed blood-stage parasites.

Syngeneic B6D2F1 (C57Bl/6 x DBA/2) mice were immunized with a nonliving antigen prepared from mixed blood forms of Plasmodium berghei strain NYU-2. Consistently greater than 80% of the vaccinated mice survived virulent challenge, and protective immunity was demonstrable from 1 week through at least 4 months after immunization. However, vaccination did not prevent the development of patient infection after challenge. Instead, infections in vaccinated mice progressed to about 10% parasitemia and were then subsequently cleared. In contrast, infections initiated in nonvaccinated mice progressed beyond 10% parasitemia and were uniformly fatal within 4 weeks. Sera collected from normal mice, nonvaccinated mice infected with P. berghei, or vaccinated mice before challenge failed to passively protect recipients against virulent infection. On the other hand, sera collected from vaccinated mice after recovery from a challenge infection conferred upon passively immunized recipients protection from homologous virulent challenge, which was manifest as a delay in the onset of overt infection. It was concluded, therefore, that vaccination altered the immunological potential of the host in such a way as to allow the production of a protective humoral factor, probably specific antibody, in response to infection with the virulent parasites.     

Interleukin-6 induces early gamma interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection

Immunity to Mycobacterium tuberculosis is dependent upon the generation of a protective gamma interferon (IFN-gamma)-producing T-cell response. Recent studies have suggested that interleukin-6 (IL-6) is required for the induction of a protective T-cell response and that IL-4 may suppress the induction of IFN-gamma. To evaluate the role of the cytokines IL-6 and IL-4 in the generation of pulmonary immunity to M. tuberculosis, IL-6 and IL-4 knockout mice were infected with M. tuberculosis via aerosol. The absence of IL-6 led to an early increase in bacterial load with a concurrent delay in the induction of IFN-gamma. However, mice were able to contain and control bacterial growth and developed a protective memory response to secondary infection. This demonstrates that while IL-6 is involved in stimulating early IFN-gamma production, it is not essential for the development of protective immunity against M. tuberculosis. In contrast, while the absence of IL-4 resulted in increased IFN-gamma production, this had no significant effect upon bacterial growth.     

Dominant nonresponsiveness to Helicobacter pylori infection is associated with production of interleukin 10 but not gamma interferon

Helicobacter pylori-induced gastritis is an essential precursor lesion for the development of peptic ulcers or gastric adenocarcinoma. We demonstrate that nonresponsiveness to H. pylori SS1 infection is dominantly inherited in mice. F(1) hybrid crosses between a nonresponder mouse and three responder strains all possessed the nonresponder phenotype. Secretion of interleukin-10 but not gamma interferon was associated with nonresponsiveness to infection.     

Stromal cell-derived factor-1 production by spleen cells is affected by nitric oxide in protective immunity against blood-stage Plasmodium chabaudi CR in C57BL/6j mice

Malaria, a major endemic tropical disease, is caused by the infection of blood cells by Plasmodium protozoa. Most patients control their parasitemia by a not fully understood spleen-dependent mechanism. SDF-1alpha is a chemokine produced by stromal cells such as reticular spleen cells. Nitric oxide (NO) has several immune functions, including killing of intracellular pathogens and its function in malaria is debated. We have previously shown that SDF-1alpha production peaks during the ascending parasitemia in Plasmodium chabaudi infection and its supplementation in lethal models could reduce the parasitemia. In the present study, we analyzed SDF-1 production by spleen cells as related to NO metabolism in the P. chabaudi rodent malaria model using IFN-gamma; TNFR and iNOS-knockout mice or iNOS-blocked, L-NAME- or aminoguanidine-treated mice. Parasitemia and production of SDF-1alpha and SDF-1beta were determined by RT-PCR. In vitro NO production by spleen adherent cells was also tested. The data showed that parasitemia was less intense in both iNOS(-/-) or NO-inhibited mice than in controls, with increased and long-lasting production of SDF-1alpha mRNA. In the absence of cytokines involved in the final regulation of NO production by effector cells, as is the case for TNFR(-/-) and GKO mice, the infection progressed in an uncontrolled manner regardless of SDF-1alpha production, suggesting that these cytokines must be involved in the control of parasitemia after the SDF-1alpha dependent process. The SDF-1beta isoform was constitutive in all experiments, with elevated levels only clearly seen in TNFR(-/-) mice. We conclude that SDF-1 is involved in the promotion of parasitemia control in malaria, and excessive NO could affect its production.     

Using two phases of the CD4 T cell response to blood-stage murine malaria to understand regulation of systemic immunity and placental pathology in Plasmodium falciparum infection

Plasmodium falciparum infection and malaria remain a risk for millions of children and pregnant women. Here, we seek to integrate knowledge of mouse and human T helper cell (Th) responses to blood-stage Plasmodium infection to understand their contribution to protection and pathology. Although there is no complete Th subset differentiation, the adaptive response occurs in two phases in non-lethal rodent Plasmodium infection, coordinated by Th cells. In short, cellular immune responses limit the peak of parasitemia during the first phase; in the second phase, humoral immunity from T cell–dependent germinal centers is critical for complete clearance of rapidly changing parasite. A strong IFN-γ response kills parasite, but an excess of TNF compared with regulatory cytokines (IL-10, TGF-β) can cause immunopathology. This common pathway for pathology is associated with anemia, cerebral malaria, and placental malaria. These two phases can be used to both understand how the host responds to rapidly growing parasite and how it attempts to control immunopathology and variation. This dual nature of T cell immunity to Plasmodium is discussed, with particular reference to the protective nature of the continuous generation of effector T cells, and the unique contribution of effector memory T cells.     

STAT1 is essential for antimicrobial effector function but dispensable for gamma interferon production during Toxoplasma gondii infection

The opportunistic protozoan Toxoplasma gondii is a prototypic Th1-inducing pathogen inducing strong gamma interferon (IFN-gamma) cytokine responses that are required to survive infection. Intracellular signaling intermediate STAT1 mediates many effects of IFN-gamma and is implicated in activation of T-bet, a master regulator of Th1 differentiation. Here, we show that T. gondii-infected STAT1-null mice fail to upregulate the IFN-gamma-dependent effector molecules inducible nitric oxide synthase (iNOS), IGTP, and LRG-47, which are required for mice to survive infection. Both T-bet and interleukin-12 receptor beta2 (IL-12Rbeta2) failed to undergo normal upregulation in response to T. gondii. Development of IFN-gamma-producing CD4(+) and CD8(+) T lymphocytes was severely curtailed in the absence of STAT1, but a substantial level of STAT1-independent non-T-cell-derived IFN-gamma was induced. Absence of STAT1 also resulted in increased IL-4, Arg1, Ym1, and Fizz1, markers of Th2 differentiation and alternative macrophage activation. Together, the results show that T. gondii induces STAT1-dependent T-lymphocyte and STAT1-independent non-T-cell IFN-gamma production, but that effector functions of this type 1 cytokine cannot operate in the absence of STAT1, resulting in extreme susceptibility to acute infection.     

MyD88 deficiency leads to decreased NK cell gamma interferon production and T cell recruitment during Chlamydia muridarum genital tract infection, but a predominant Th1 response and enhanced monocytic inflammation are associated with infection resolution

We have previously shown that MyD88 knockout (KO) mice exhibit delayed clearance of Chlamydia muridarum genital infection compared to wild-type (WT) mice. A blunted Th1 response and ineffective suppression of the Th2 response were also observed in MyD88 KO mice. The goal of the present study was to investigate specific mechanisms whereby absence of MyD88 leads to these effects and address the compensatory mechanisms in the genital tract that ultimately clear infection in the absence of MyD88. It was observed that NK cells recruited to the genital tract in MyD88 KO mice failed to produce gamma interferon (IFN-γ) mRNA and protein. This defect was associated with decreased local production of interleukin-17 (IL-17), IL-18, and tumor necrosis factor alpha (TNF-α) but normal levels of IL-12p70. Additionally, recruitment of CD4 T cells to the genital tract was reduced in MyD88 KO mice compared to that in WT mice. Although chronic infection in MyD88 KO mice resulted in oviduct pathology comparable to that of WT mice, increased histiocytic inflammation was observed in the uterine horns. This was associated with increased CCL2 levels and recruitment of macrophages as a potential compensatory mechanism. Further deletion of TLR4-TRIF signaling in MyD88 KO mice, using TLR4/MyD88 double-KO mice, did not further compromise host defense against chlamydiae, suggesting that compensatory mechanisms are Toll-like receptor (TLR) independent. Despite some polarization toward a Th2 response, a Th1 response remained predominant in the absence of MyD88, and it provided equivalent protection against a secondary infection as observed in WT mice.     

A critical role for stem cell factor and c-kit in host protective immunity to an intestinal helminth

In common with many intestinal nematode infections, Trichinellaspiralls infections in mice are associated with a pronouncedintestinal mast cell hyperplasia. The expulsion of the parasitefrom the gut is temporally associated with intestinal mastocytosisand mast cell function reflected by the secretion of mast cellprotease into tissue and serum. In vivo, mucosal mast cell productionis highly dependent upon T cell-derived cytokines includingIL-3 and lL-4. We present data here to show that intestinalmast cell hyperplasia induced by helminth infection is alsodependent upon the production of stem cell factor (SCF). Neutralizationof SCF by anti-SCF or anti-SCF receptor mAb completely abrogatedthe mast cell hyperplasia generated by T spiralls infection.Moreover, worm expulsion was dramatically delayed in treatedmice and a reduced intestinal eoslnophilla was observed. Theseeffects did not appear to be mediated through alteration ofT^h cell responses and the parasite-specific serum antibody responsewas not affected. The reduction in the mast cell response andworm expulsion observed after SCF neutralization were reversiblefollowing cessation of monoclonal treatment. The data presentedhere clearly demonstrate a major role for SCF in the generationof intestinal mastocytosis and the host protective immune responsefollowing parasitic infection.     

Cellular immunity,but not gamma interferon,is essential for resolution of Babesia microti infection in BALB/c mice

A new strain of Babesia microti (KR-1) was isolated from a Connecticut resident with babesiosis by hamster inoculation and adapted to C3H/HeJ and BALB/c mice. To examine the relative importance of humoral and cellular immunity for the control of B. microti infection, we compared the course of disease in wild-type BALB/c mice with that in BALB/c SCID mice, JHD-null (B-cell-deficient) mice, and T-cell receptor alphabeta (TCRbeta(-/-)) or gamma interferon (IFN-gamma) (IFN-gamma(-/-)) knockout mice following inoculation with the KR-1-strain. SCID mice and TCRalphabeta knockouts sustained a severe but nonlethal parasitemia averaging 35 to 45% infected erythrocytes. IFN-gamma-deficient mice developed a less severe parasitemia but were able to clear the infection. In contrast, in six of eight JHD-null mice, the levels of parasitemia were indistinguishable from those in the wild-type animals. These data indicate that cellular immunity is critical for the clearance of B. microti in BALB/c mice but that disease resolution can occur even in the absence of IFN-gamma.     

B cell activation in clinically quiescent systemic lupus erythematosus (SLE) is related to immunoglobulin levels, but not to levels of anti-dsDNA, nor to concurrent T cell activation.

In clinically quiescent SLE hypergammaglobulinaemia, presence of autoantibodies, and increased soluble IL-2 receptors (sIL-2R) have been reported, suggesting persistent B as well as T cell activation. In contrast, the primary immune response to test antigens is markedly decreased. To analyse these phenomena at a cellular level, we undertook a cross-sectional study on 13 non-active SLE patients and 15 controls. We determined the composition of lymphocyte subsets with special attention to activation markers (CD25, HLA-DR, CD38) and the presence of naive T cells (CD45RO-), and related those findings to serological parameters. In non-active SLE patients the expression of activation markers on B cells and T cells was higher than in normal controls (P < or = 0.02), but was not interrelated. Percentages of activated B cells in SLE were related to levels of total IgG (P < 0.02) and IgM (P < 0.02) but not to anti-dsDNA, suggesting a disordered immune system also in clinically quiescent SLE. Numbers of CD4+ cells (P < 0.001) and CD4+CD45RO- cells (P < 0.05) were decreased. The latter finding might explain the anergy to primary test antigens in clinically quiescent SLE.     

Gamma interferon, tumor necrosis factor alpha, and nitric oxide synthase 2, key elements of cellular immunity, perform critical protective functions during humoral defense against lethal pulmonary Yersinia pestis infection

Pulmonary infection by Yersinia pestis causes pneumonic plague, a rapidly progressing and often fatal disease. To aid the development of safe and effective pneumonic plague vaccines, we are deciphering mechanisms used by the immune system to protect against lethal pulmonary Y. pestis infection. In murine pneumonic plague models, passive transfer of convalescent-phase sera confers protection, as does active vaccination with live Y. pestis. Here, we demonstrate that protection by either protocol relies upon both gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) cytokines classically associated with type 1 cellular immunity. In both protocols, abrogating IFN-gamma or TNF-alpha activity significantly decreases survival and increases the bacterial burden in pulmonary, splenic, and hepatic tissues. Neutralization of either cytokine also counteracts challenge-induced, vaccination-dependent upregulation of nitric oxide synthase 2 (NOS2). Moreover, genetic depletion of NOS2 suppresses protection conferred by serotherapy. We conclude that IFN-gamma, TNF-alpha, and NOS2, key elements of cellular immunity, perform critical protective functions during humoral defense against lethal pulmonary Y. pestis challenge. These observations strongly suggest that plague vaccines should strive to maximally prime both cellular and humoral immunity.     

The protein kinase PKR is critical for LPS‐induced iNOS production but dispensable for inflammasome activation in macrophages

Inflammasomes are multi‐protein platforms that drive the activation of caspase‐1 leading to the processing and secretion of biologically active IL‐1β and IL‐18. Different inflammasomes including NOD‐like receptor (NLR) family pyrin domain‐containing 3 (NLRP3), NLR caspase‐recruitment domain‐containing 4 (NLRC4) and absent in melanoma 2 (AIM2) are activated and assembled in response to distinct microbial or endogenous stimuli. However, the mechanisms by which upstream stimuli trigger inflammasome activation remain poorly understood. Double‐stranded RNA‐activated protein kinase (PKR), a protein kinase activated by viral infection, has been recently shown to be required for the activation of the inflammasomes. Using macrophages from two different mouse strains deficient in PKR, we found that PKR is important for the induction of the inducible nitric oxide synthase (iNOS). However, PKR was dispensable for caspase‐1 activation, processing of pro‐IL‐1β/IL‐18 and secretion of IL‐1β induced by stimuli that trigger the activation of NLRP3, NLRC4 and AIM2. These results indicate that PKR is not required for inflammasome activation in macrophages.     

Early IL-12 p70, but not p40, production by splenic macrophages correlates with host resistance to blood-stage Plasmodium chabaudi AS malaria.

In this study, we compared synthesis of IL-12, a potent Th1-inducing cytokine, by splenic macrophages recovered from resistant C57Bl/6 (B6) mice, which develop predominantly Th1 responses, and susceptible A/J mice that mount primarily Th2 responses during early Plasmodium chabaudi AS infection. Quantitative analysis of IL-12 p40 and p70 release by ELISA revealed significant differences between resistant B6 and susceptible A/J mice in the synthesis of biologically active IL-12 p70, but not p40, by splenic macrophages during early blood-stage P. chabaudi AS infection. Despite up-regulation in p40 and p35 mRNA levels, spontaneous release of p40 in vitro by splenic macrophages was not significantly increased following infection in either mouse strain. In contrast, spontaneous release of p70 by splenic macrophages was increased in cells from B6 mice and levels were significantly higher compared with A/J mice. Furthermore, compared with infected A/J hosts, splenic macrophages recovered from infected B6 mice produced significantly greater quantities of IL-12 p70, but not p40, in vitro, following stimulation with lipopolysaccharide (LPS) or malaria parasite antigen (PRBC). Moreover, we found significant increases in the percentage of macrophages earlier in the spleens of infected B6 mice that could further contribute to differences in total p70 levels in vivo. Taken together, these data suggest that macrophage IL-12 synthesis may contribute to the polarization of Th responses seen in resistant B6 and susceptible A/J mice during acute blood-stage malaria.     

T cell activation by antigens on human melanoma cells co-stimulation by B7-1 is neither sufficient nor necessary to stimulate IL-2 secretion by melanoma-specific T cell clones in vitro

B7-1 expression, induced by transfection in poorly Immunogenicmurine tumours, was shown to elicit a T cell-mediated rejectionof these tumours and further active immunity against the nontransfectedtumour. We therefore asked to what level similarly induced expressionof B7 on human melanoma cells would affect the antigen-dependentresponses of tumour-specific T cell clones in vitro. Data presentedshow that B7-1 expression by melanoma lines: (i) significantlyinduced, or improved, an IL-2-dependent proliferative responseof such clones to the antigen; (ii) increased the amount ofIL-2 produced by two clones in response to the parental non-transfectedtumour cells;and (iii) increased the TNF responses of all theCD4⁺ clones. However, despite these clear co-stimulatory effectson antigen-induced responses of all T cell clones, which demonstratedaneffective interaction of the B7-1 transfected molecule withone or the other of its counter-receptors expressed on T cellclones, B7 co-stimulation did not correct the defect of IL-2secretion exhibited by many of these clones in response to invitro antigen presentation by melanoma cells. We further showthat defective IL-2 secretion in response to melanoma antigenswas not due to a T cell clone refractoriness induced by theculture, since one of these clones could be induced to secreteIL-2 by an antigen-expressing melanoma line, upon increasedlymphocyte function associated antigen-3expression induced bygene transfectlon. Together these data suggest that defectiveIL-2 secretion by many tumour-infiltrating lymphocytes clonesin response to antigen presentation by melanoma cells in vitrois not exclusively due to the inability of these cells to providean appropriate co-stimulation through the B7-1 molecule.     

Evidence that NK cells and interferon are required for genetic resistance to lethal infection with ectromelia virus

Summary C 57 BL/6 mice developed resistance to lethal intravenous challenge with virulent (Moscow strain) ectromelia virus between 2 and 3 weeks of age. The fraction of C 57 BL/6 mice in which virus was detected in spleen was significantly lower than for DBA/2 mice by day 3. Thereafter, C 57 BL/6 mice had significantly reduced virus titers in spleen compared with those of DBA/2 mice. Resistance was abrogated by treatment with anti-asialo GM₁ gammaglobulin, which blocks NK cell activity, or with anti-interferon (IFN) , . C 57 BL/6 mice carrying the bg/bg mutation, associated with a deficiency of NK cells, were highly susceptible to lethal infection as were athymic mice derived from a resistant genetic background. Virus titers in spleens of C 57 BL/6 mice treated with anti-asialo GM₁ or anti-IFN , were significantly higher 4 days after virus challenge than were titers in C 57 BL/6 mice treated with normal rabbit serum. The results strongly suggest that genetic resistance to lethal ectromelia virus infection requires non-specific host defenses such as NK cells and IFN , that are activated during the first 3 to 4 days of infection.     

Innate immunity to Toxoplasma gondii is influenced by gender and is associated with differences in interleukin-12 and gamma interferon production.

Given that differences between the sexes in relative susceptibility to parasitic infections have been noted, this study further elucidates the mechanisms responsible by demonstrating that male SCID mice are more resistant than female mice to infection with Toxoplasma gondii and that this difference correlates with enhanced innate immune responses in these animals. Male SCID mice exhibited longer survival times, lower parasite burdens, and less severe pathological changes postinfection. An immunological basis for these differences is demonstrated in that these animals produced interleukin-12 more rapidly and exhibited higher levels of gamma interferon earlier postinfection.