Inhibition of H-Y cell-mediated cytolysis by monoclonal H-Y-specific antibody

Assays of H-Y-specific, cell-mediated cytolysis (CMC) in vitro were carried out with B6 female effector cells and B6 male target cells. Monoclonal H-Y antibody was added to the lytic assay to test whether the antigenic determinant(s) involved in H-Y-specific CMC was distinct from the serologically detected H-Y antigen. Significant blocking was observed, suggesting that the H-Y antigen detectable serologically is similar to H-Y antigen recognized by cytotoxic T cells.Abbreviations used in this paper B6 C57BL/6 - BALB BALB/c - CMC cell-mediated cytolysis - E effector cells - T target cells     

Allogeneic manipulation of the GAT idiotypic cascade. Immunization of C57BL/6 mice by BALB/c anti-idiotypes stimulates similar strain-specific V genes as the original antigen

Antibodies specific for the immunizing Ag (Ab1) (Id+ Ag+) and Ab3 (Id+ Ag+ or Id+ Ag-) of the (Glu60 Tyr10 Ala30) (GAT) idiotypic cascade express similar pGAT public determinants in BALB/c and C57BL/6 strains. These determinants have been shown to be dependent upon both VH and Vkappa encoded segments. The VH of the BALB/c Ab1 (germ-line gene H10) and that of the C57BL/6 Ab1 (germ-line gene V186-2) are only 75% homologous, whereas VK are much more conserved. C57BL/6 mice were immunized with BALB/c Ab2 (anti-idiotypic) antibodies and monoclonal Ab3 were derived after fusion of immunized spleen cells with the nonsecreting hybridoma cell line Sp/2.0-Ag. From 13 cell lines, five clones (four Id+ Ag- and one Id+ Ag+) were isolated and the mRNA V regions sequenced. Immunization with BALB/c anti-idiotypes elicits expression of the same or closely related C57BL/6 VH and Vkappa genes as when C57BL/6 mice were immunized with GAT, although functional VH BALB/c equivalents have been isolated in the B6 strain. Our results suggest that manipulation of the repertoire via antigenic or idiotypic stimulation both lead to the expression of different genes in different strains. They further confirm that the immune system is largely degenerate, for both idiotype expression and Ag recognition.     

A limited region within hen egg-white lysozyme serves as the focus for a diversity of T cell clones

The C57BL/6 (H-2b) mouse is a nonresponder to hen egg-white lysozyme (HEL) injected i.p., owing to a T suppressor cell-inducing determinant at the amino-terminal region. After immunization with a 93-amino acid fragment (a.a. 13-105) of HEL lacking this determinant, all clones from two independently derived C57BL/6 T cell lines were found to be specific for epitopes within a subregion of peptide 74-96. Three specificity patterns for the clones could be defined on the basis of cross-reactivities with only two other species variant lysozymes. Reactivities of all three specificity groups was consistent with the serine to threonine substitution at position 91, although reactivity of one of the groups could be affected by substitutions at position 84. The results confirm at the clonal level that even for distantly related antigens, only limited regions are recognized by T cells. They are consistent with the notion that specific sites on the antigen capable of interaction with Ia molecules lead to dominance of certain regions for T cell reactivity. Moreover, the diversity in specificity among clones suggests that the limiting feature of T cell responsiveness is not a lack of available T cells in the repertoire directed against a single antigenic site.     

Plasmodium-host interactions directly influence the threshold of memory CD8 T cells required for protective immunity

Plasmodium infections are responsible for millions of cases of malaria and ～1 million deaths annually. Recently, we showed that sterile protection (95%) in BALB/c mice required Plasmodium berghei circumsporozoite protein (CS(252-260))-specific memory CD8 T cells exceeding a threshold of 1% of all PBLs. Importantly, it is not known if Plasmodium species affect the threshold of CS-specific memory CD8 T cells required for protection. Furthermore, C57BL/6 mice immunized with radiation-attenuated parasites are more difficult to protect against Plasmodium sporozoite challenge than similarly immunized BALB/c mice; however, it is not known whether this is the result of different CD8 T cell specificity, functional attributes of CD8 T cells, or mouse strain-specific factors expressed in nonhematopoietic cells. In this article, we show that more CS-specific memory CD8 T cells are required for protection against P. yoelii sporozoite challenge than for protection against P. berghei sporozoite challenge. Furthermore, P. berghei CS(252)-specific CD8 T cells exhibit reduced protection against P. berghei sporozoite challenge in the context of C57BL/6 and C57BL/10 non-MHC-linked genes in CB6F1 and B10.D2 mice, respectively. Generation and immunization of reciprocal chimeric mice between BALB/c and B10.D2 strains revealed that B10 background factors expressed by nonhematopoietic cells increased the threshold required for protection through a CD8 T cell-extrinsic mechanism. Finally, reduced CS-specific memory CD8 T cell protection in P. yoelii-infected BALB/c or P. berghei-infected B10.D2 mice correlated with increased rates of Plasmodium amplification in the liver. Thus, both Plasmodium species and strain-specific background genes in nonhematopoietic cells determine the threshold of memory CD8 T cells required for protection.     

Activation of murine T cells by toxic shock syndrome toxin-1. The toxin-binding structures expressed on murine accessory cells are MHC class II molecules

Toxic shock syndrome toxin-1 (TSST-1)-binding structures present on murine lymphoid tissues were investigated by using 125I-TSST-1. T-depleted C57BL/6 spleen cells incubated with TSST-1 for 3 h at 0 degree C were mitogenic to splenic T cells, indicating that the former cells bind and present TSST-1 to T cells. TSST-1-binding activity was observed in C57BL/6 splenic B cells and L cells transfected with I-Ab genes, but not in splenic T cells and control L cells. Scatchard plot analysis showed that these B cells and transfectants bound TSST-1 with similar binding affinity. SDS-PAGE analysis showed that lysates of C57BL/6 spleen cells and the I-Ab-positive transfectants contain a single band which bound TSST-1 and comigrated with I-Ab heterodimers. TSST-1-binding activity observed clearly in C57BL/6. BALB/c, and C3H/HeN spleen cells and L cells transfected with I-Ab or I-Ak genes was not reduced by paraformaldehyde fixation. Binding of 125I-TSST-1 to the three spleen cells was markedly reduced by anti-I-A antibodies, but not by anti-I-E antibodies. C57BL/6, C3H/HeN, and (C3H/HeN x C57BL/6) F1 T cells were activated by TSST-1 to proliferate and produce IL-2 in the presence of FT6.2 cells, LT1-30-3 cells and either of them, respectively, but not in the presence of control L cells. These results indicate that I-A molecules function as the structures via that accessory cells directly bind TSST-1 on the cell surface and present a triggering signal of TSST-1 to T cells.     

Induction of alloreactive cytotoxic T cells by acute virus infection of mice

Alloreactive cytotoxic T lymphocytes (CTL) distinct from virus-specific CTL and activated natural killer (NK) cells were generated during acute lymphocytic choriomeningitis virus (LCMV) infection of C57BL/6J mice. The alloreactive CTL shared similar antigenic markers (Thy-1.2+, Lyt-2.2+, and asialo GM1-) with the virus-specific CTL that appeared at the same time 7 days postinfection, but had different target specificities. These alloreactive CTL lysed allogeneic but not syngeneic or xenogeneic targets. These were distinct from activated NK cells, which lysed all target cell types, peaked 3 days postinfection, and had a phenotype of asialo GM1+, Thy-1 +/-, Lyt-2.2-. Cold target competition studies indicated that there were several subsets of alloreactive T cells with distinct specificities, and that these alloreactive T cells were not subsets of the virus-specific T cells. Similar types of alloreactive CTL were induced at much lower levels in C3H/St mice. This may indicate that the generation of this "aberrant" T cell activity is under genetic control. Hence, the LCMV infection of C57BL/6J mice induces several cytotoxic effector populations including alloreactive CTL, activated NK cells, and virus-specific CTL. Virus infections therefore have the ability not only to polyclonally stimulate B cells, as previously described, but also to stimulate CTL.     

Visualization, fate, and pathogenicity of antigen-specific CD8+ T cells in the graft-versus-host reaction.

To follow the fate of alloreactive T cell effectors in graft-vs-host disease, Ld-specific CD8+ T cells from C57BL/6 2C TCR-transgenic donors were transplanted into sublethally irradiated (750 cGy) Ld+ or Ld- recipients. In Ld- C57BL/6 or (BALB/c-dm2 x C57BL/6)F1 recipients, naive 2C T cells engrafted and survived long term, but did not acquire effector function. In Ld+ (BALB/c x C57BL/6)F1 recipients, 2C T cells engrafted, expanded, became cytolytic, destroyed host B cells and double-positive thymocytes, and later disappeared. Despite marked damage to lymphoid and hemopoietic cells by 2C T cells, no significant pathology was detected in other organs, and recipients survived. Ld+ (BALB/c x C57BL/6)F1 recipients died when LPS/endotoxin was administered on day 7 after cell transfer, while Ld- (BALB/c-dm2 x C57BL/6)F1 recipients survived. Our findings show that under certain conditions, a CD8+ T cell population recognizing an extremely limited repertoire of Ags can initiate graft-vs-host disease.     

Regulatory roles of IL-2 and IL-4 in H4/inducible costimulator expression on activated CD4+ T cells during Th cell development

We found a tight correlation among the levels of H4/inducible costimulator (ICOS) expression, IL-4 production, and GATA-3 induction, using activated CD4(+) T cells obtained from six different murine strains. BALB/c-activated CD4(+) T cells expressed approximately 10-fold more H4/ICOS on their surfaces and produced approximately 10-fold more IL-4 upon restimulation than C57BL/6-activated CD4(+) T cells. BALB/c naive CD4(+) T cells were shown to produce much higher amounts of IL-2 and IL-4 upon primary stimulation than C57BL/6 naive CD4(+) T cells. Neutralization of IL-4 with mAbs in culture of BALB/c naive CD4(+) T cells strongly down-regulated both H4/ICOS expression on activated CD4(+) T cells and IL-4 production upon subsequent restimulation. Conversely, exogenous IL-4 added to the culture of BALB/c or C57BL/6 naive CD4(+) T cells up-regulated H4/ICOS expression and IL-4 production upon restimulation. In addition, retroviral expression of GATA-3 during the stimulation of naive CD4(+) T cells from C57BL/6 or IL-4(-/-) mice increased H4/ICOS expression on activated CD4(+) T cells. A similar effect of IL-2 in the primary culture of BALB/c naive CD4(+) T cells appeared to be mediated by IL-4, the production of which was regulated by IL-2. These data suggest that IL-4 induced by IL-2 is critical to the maintenance of high H4/ICOS expression on BALB/c-activated CD4(+) T cells.     

Regulation of T15 idiotype dominance. II. Genes unlinked to the Igh locus regulate T15 dominance of the secondary adoptive transfer response to phosphocholine

We have studied the idiotype and fine specificity of the secondary immune response to phosphocholine (PC) in C57BL (B10, B10.D2, and B.C8) and BALB (BALB/c, BAB-14, and C.B20) congenic strains of mice. In vivo IgM responses of mice from these two genetic backgrounds differed in their T15 idiotypic representation. BALB strains expressed the T15 idiotype on greater than 90% of their IgM, PC-specific plaque-forming cells (PFC), whereas C57BL strains expressed the T15 idiotype on approximately 50% of their IgM PFC. All strains examined expressed greater than 75% PC-inhibitable, VHPC idiotype-positive, IgM PFC. The IgG3 and IgA memory responses were similar to the IgM memory response; BALB strains produced a higher proportion of T15+ PFC than C57BL strains; however, the majority of IgG3 and IgA PFC in all strains were VHPC+, and PC-inhibitable. In contrast, the IgG1 memory response was not dominated by T15+, VHPC+, PC-inhibitable PFC in any of the strains tested. The IgG1 PFC required nitrophenylphosphocholine (NPPC) for efficient inhibition. The IgG2 memory response generally mimicked the IgG1 response with respect to idiotype and specificity. These data demonstrate that the representation of the T15 idiotype in the anti-PC immune response is determined by genes outside both the MHC and Igh genetic loci. Control of T15 expression in secondary IgM, IgG3, and IgA anti-PC responses was examined by using a cell-mixing protocol with primed T and B cells from BALB/c and B10.D2 mice. T15 representation in these responses was determined by the genotype of the B cell, not by the genotype of the helper T cell. Similarly, the B cell genotype was responsible for the idiotypic profile of a primary, in vitro, T-dependent, anti-PC response.     

Relative positioning of the T cell and B cell determinants on an immunogenic peptide: its influence on antibody response

A tryptic peptide of bovine beta-casein (amino acid residues 184-202) was used as a model antigen to investigate how the relative position of the (helper) T cell and B cell determinants on a protein antigen influences the antibody response. Immunization with the peptide elicited a considerably higher anti-peptide response in the C3H/He strain than in the C57BL/6 strain, despite the fact that the C57BL/6 T cells showed higher reactivity than the C3H/He T cells. The T cell and B cell determinants of the peptide were identified in these two strains. Each strain recognized a single B cell determinant and a single T cell determinant. In the C3H/He strain, the T and B cell determinants were located apart from one another, while the T and B cell determinants of the C57BL/6 strain were located in a region close each other. The results suggest that the level of an antibody response depends on the topological relationship of the T cell and B cell determinants on the antigen molecule.     

Fate of H2-activated T lymphocytes in syngeneic hosts. III. Differentiation into long-lived recirculating memory cells.

Memory to H2 determinants was studied with an adoptive transfer system using a population of H2-activated blast T cells (T.TDL) obtained from thoracic duct lymph of irradiated F₁ hybrid mice injected with parental strain T cells. CBA T.TDL activated either to DBA/2 or C57BL determinants were transferred to syngeneic “B” mice. Thoracic duct lymphocytes (TDL) were obtained from the recipients 4–6 weeks later and tested for their capacity to produce (a) a graft-versus-host (GVH) reaction, (b) a mixed lymphocyte reaction (MLR) (measured by an in vivo technique) and (c) allograft rejection (suppression of the growth of allogeneic tumour cells in vivo). Control experiments involved testing the function of TDL obtained from “B” mice preinjected with TDL or no cells.TDL from “B” mice injected with TDL (passaged TDL) gave strong MLR and GVH reactions to both DBA/2 and C57BL determinants. Passaged T.TDL activated to C57BL antigens gave intermediate MLR and GVH reactions to the specific (C57BL) determinants but only very low responses to third-party (DBA/2) determinants; reciprocal results were obtained with passaged T.TDL activated to DBA/2 determinants. TDL from “B” mice given no cells failed to respond to either set of determinants.Since the responses by the passaged T.TDL did not exceed those by passaged TDL there was no evidence that adoptive transfer of T.TDL had conferred to the recipients a state of memory to either MLR or GVH determinants. Adoptive transfer did, however, lead to qualitative changes in the properties of T.TDL since, before transfer, they were unable to evoke GVH reactions or produce an MLR of normal kinetics.Passaged T.TDL were far superior to passaged TDL at suppressing the growth of allogeneic tumour cells. The protection was specific since protection against DBA/2 tumour cells was, cell for cell, 5–10 fold more effective with passaged T.TDL activated to DBA/2 determinants than with cells activated to C57BL determinants. No protection was observed with cells treated with anti-θ serum. The protective cells appeared to be precursors of effector cells rather than effector cells per se since they failed to lyse the tumour cells in vitro. These data suggest therefore that the descendants of T.TDL which survived after transfer to “B” mice were highly enriched in long-lived recirculating T lymphocytes reactive to determinants expressed by specific tumour allografts.     

Activation of CD8 T cells by mycobacterial vaccination protects against pulmonary tuberculosis in the absence of CD4 T cells

We have investigated whether both primary CD8 T cell activation and CD8 T cell-mediated protection from Mycobacterium tuberculosis challenge could occur in mycobacterial-vaccinated CD4 T cell-deficient (CD4KO) mice. Different from wild-type C57BL/6 mice, s.c. vaccination with bacillus Calmette-Guérin (BCG) in CD4KO mice failed to provide protection from secondary M. tuberculosis challenge at 3 wk postvaccination. However, similar to C57BL/6 mice, CD4KO mice were well protected from M. tuberculosis at weeks 6 and 12 postvaccination. This protection was mediated by CD8 T cells. The maintenance of protective effector/memory CD8 T cells in CD4KO mice did not require the continuous presence of live BCG vaccine. As in C57BL/6 mice, similar levels of primary activation of CD8 T cells in CD4KO mice occurred in the draining lymph nodes at 3 wk after BCG vaccination, but different from C57BL/6 mice, the distribution of these cells to the spleen and lungs of CD4KO mice was delayed, which coincided with delayed acquisition of protection in CD4KO mice. Our results suggest that both the primary and secondary activation of CD8 T cells is CD4 T cell independent and that the maintenance of these CD8 T cells is also independent of CD4 T cells and no longer requires the presence of live mycobacteria. However, the lack of CD4 T cells may result in delayed distribution of activated CD8 T cells from draining lymph nodes to distant organs and consequently a delayed acquisition of immune protection. Our findings hold implications in rational design of tuberculosis vaccination strategies for humans with impaired CD4 T cell function.     

Separation of T and B lymphocytes from various mouse strains by density gradient electrophoresis

T and B mouse spleen lymphocytes were separated by density gradient electrophoresis on the basis of their surface charge. In all strains examined, the T lymphocytes were found in the high mobility fractions and the B in the low. The T and B cells were separated completely in most fractions, with some overlapping in the middle. Significant differences were found in the electrophoretic distribution profiles between the strains: C57BL/6j, C57BL/10j, (BALB/cXC57BL/6j)F₁, and all the following: B₆·C-H-2^d/cBy (congenic to C57BL/6j), BALB/c, CBA/H/T6j, C57BL/10Sn, and C3H. The C57BL/6j and the (BALB/cXC57BL/6j)F₁ cells appear more heterogeneous as far as electrophoretic mobility is concerned. Almost all the other strains give two major peaks. Moreover, the high mobility areas are less populated in the C57BL/6j and the (BALB/cXC57BL/6j)F₁ animals than in all the others. The above differences were found consistently when cells prepared by different methods were electrophoresed. It is concluded that the surface charge of lymphocytes may be genetically determined. Possible dependency on the H-2 complex or non-H-2 areas is discussed.     

Production of heterologous antibodies to T-killers of mice immunized against H-2 antigens

Rabbit antisera were obtained against cytotoxic small peritoneal lymphocytes (IPEL) of CBA (H-2k) mice immune to alloantigens C57BL/6 (H-2b) and to the enriched 5-day MLC cytotoxic blast lymphocytes (MLC--CL). After appropriate absorption by cells and tissues of intact mice the cytotoxicity of the sera was lost relative to normal lymphoid cells. The absorbed anti-CPL serum inhibited, in the presence of complement, the cytotoxic effect of CPL but not that of MLC--CL on 51Cr-labeled allogeneic macrophages. This inhibition was restricted by idiotypic and strain specificity. Conversely, the absorbed anti-MLC--CL serum inhibited the cytotoxic effect of both CPL and MLC--CL of various mouse strains, irrespective of their immunologic specificity. It is supposed that the effect of the anti-CPL serum is mainly caused by antibodies againts idiotypic determinants of the killer T receptors, whereas the effect of the anti-MLC--CL serum is due to antibodies against differentiation antigens of the proliferating lymphocytes.     

Mapping of theLyb-4 gene to different chromosomes in DBA/2J and C3H/HeJ mice

Linkage has been established between the Lyb-4 alloantigen locus and the chromosome 4 markersLyb- 2 andMup- 1 using recombinant inbred (RI) strains. Only 2 of 24 BXD RI strains possess recombinant genotypes with respect to the B cell alloantigen lociLyb- 4 andLyb- 2, for an estimated recombination frequency of 0.024 ±0.019. One additional BXD RI strain was a recombinant with respect toLyb- 4 andMup- 1 (major urinary protein locus) for an estimated recombination frequency of 0.039 ± 0.026. These linkages were confirmed and further quantitated in a (C57BL/6J × DBA/2J)F₁ × C57BL/6J backcross population, in which the recombination frequency betweenLyb- 4 andMup- 1 was 0.049 ± 0.019. No recombination between the expression of Lyb-4.1 antigen and the ability of anti-Lyb-4.1 serum to suppress MLC reactivity was found, indicating that the genes controlling the antigenic determinant which is recognized with cytotoxic antibodies in anti-Lyb-4.1 serum is the same as, or is very closely linked to, the gene which is responsible for augmentation of the MLC response. In contrast, no linkage was observed between the gene controlling the Lyb-4.1 determinant andMup- 1 in RI strain and backcross mice derived from the cross of C3H/HeJ and C57BL/6J. Again, there was complete concordance between the serologically recognized determinant and the ability of anti-Lyb-4.1 serum to suppress the MLC response. Absorption of anti-Lyb-4.1 serum with C3H/HeJ, DBA/2J, and C57BL/6J lymphocytes, followed by the cytotoxic assay of the absorbed sera on lymphocytes of each of these three strains showed that serologically the Lyb-4.1 antigenic determinant on DBA/2 mice was indistinguishable from that on C3H/HeJ mice. Thus, both traits appear to be under the control of single genes in both DBA/2J and C3H/HeJ, but the C3H/HeJ gene appears to be nonallelic and unlinked to the DBA/2J gene.Abbreviations used in this paper LAD lymphocyte activating determinants - LPS lipopolysaccharide - MLC mixed lymphocyte culture - RI recombinant inbred     

Mechanisms of Allografted Tumor Rejection: The Roles of T Cells in Allograft Rejection Mediated by a Type of Bone Marrow-Derived Macrophage

Allografted tumor rejection does not occur in the absence of T cells, but the main effector cells responsible for the rejection are allograft-induced macrophages (AIM). We examined the roles of T cells in the AIM-mediated rejection of Meth A (H-2) tumor cells from C57BL/6 (H-2^b) mice. Irradiation of C57BL/6 mice abrogated both the induction of AIM and the allograft rejection. Reconstitution of the irradiated mice with F1 (C57BL/6 X C3H/He: H-2^b/k) bone marrow cells led to the appearance of H-2^b/k haplo-type of AIM exclusively in the rejection site and to allograft rejection, indicating that radiosensitive cells prerequisite for both the induction of AIM and allograft rejection were bone marrow-derived cells, and that the progenitors of AIM existed in the bone marrow cells to be activated into AIM in the rejection site. To understand the role of T cells in the induction of AIM, we used adult-thymectomized, X-irradiated C57BL/6 mice reconstituted with F1 bone marrow (ATXBM). The ATXBM mice could neither induce AIM nor reject allogeneic Meth A cells, whereas adoptive transfer of F1 lymph node T cells to the ATXBM mice restored not only the induction of AIM but also rejection of the allograft. Among the lymph node T cells, CD4⁺, but not CD8⁺, cells were found to be essential for the activation of AIM progenitors to AIM; and CD8⁺ T cells were further required for rejection, at least in part, to enhance the number of AIM in the rejection site.     

Leishmania major: analysis of lymphocyte and macrophage cellular phenotypes during infection of susceptible and resistant mice

Genetically susceptible BALB/c and resistant C57BL/6 mice were infected with Leishmania major and the phenotypes of the responding cells in the draining lymph nodes and cutaneous lesions were analyzed. As early as 1 week, significantly increased numbers of L3T4+ cells as compared to Lyt-2+ cells were present in BALB/c mice lymph nodes (P less than 0.005). Increases in L3T4+ and Lyt-2+ cells were comparable in C57BL/6 mice, resulting in threefold lower L3T4/Lyt-2 ratio than in BALB/c mice. T cell subsets were activated in both strains to express interleukin-2 receptor (IL2R) above resting values, although greater numbers of activated L3T4+ cells were present in the draining lymph nodes from BALB/c at 1 and 3 weeks of infection than in C57BL/6 (P = 0.02). Despite the presence of activated L3T4+ cells in both strains, macrophages differed in the expression of immunologically important surface molecules during infection. Tissue macrophages from BALB/c mice were IgG1/G2b Fc receptor (FcR)+ and Ia- late in disease, whereas macrophages in C57BL/6 became FcR and Ia during healing. BALB/c mice, treated with monoclonal antibody GK1.5 to transiently deplete L3T4+ cells, became resistant to subsequent infection and developed a macrophage phenotype that was FcR- and Ia+. These differences in macrophage phenotype were closely linked to susceptibility during infection with L. major and may play a role in the pathophysiology of murine leishmaniasis.     

Exacerbated susceptibility to infection-stimulated immunopathology in CD1d-deficient mice

Mice lacking functional CD1d genes were used to study mechanisms of resistance to the protozoan parasite Toxoplasma gondii. Wild-type (WT) BALB/c mice, CD1d-deficient BALB/c mice, and WT C57BL/6 mice all survived an acute oral infection with a low dose of mildly virulent strain ME49 T. gondii cysts. In contrast, most CD1d-deficient C57BL/6 mice died within 2 wk of infection. Despite having parasite burdens that were only slightly higher than WT mice, CD1d-deficient C57BL/6 mice displayed greater weight loss and intestinal pathology. In C57BL/6 mice, CD4(+) cells can cause intestinal pathology during T. gondii infection. Compared with WT mice, infected CD1d-deficient C57BL/6 mice had higher frequencies and numbers of activated (CD44(high)) CD4(+) cells in mesenteric lymph nodes. Depletion of CD4(+) cells from CD1d-deficient mice reduced weight loss and prolonged survival, demonstrating a functional role for CD4(+) cells in their increased susceptibility to T. gondii infection. CD1d-deficient mice are deficient in Valpha14(+) T cells, a major population of NKT cells. Involvement of these cells in resistance to T. gondii was investigated using gene-targeted Jalpha18-deficient C57BL/6 mice, which are deficient in Valpha14(+) T cells. These mice did not succumb to acute infection, but experienced greater weight loss and more deaths than B6 mice during chronic infection, indicating that Valpha14(+) cells contribute to resistance to T. gondii. The data identify CD4(+) cells as a significant component of the marked susceptibility to T. gondii infection observed in CD1d-deficient C57BL/6 mice, and establish T. gondii as a valuable tool for deciphering CD1d-dependent protective mechanisms.     

Immune response of the mouse to the major core protein (p30) of ecotropic leukemia viruses.

Sera from normal C57BL/6 mice contained low titers of antibodies against proteins of MuLV. Sera from C57BL/6 mice that were immunized with allogeneic leukemia cells sometimes contained high-titered antibodies against the p15 protein of MuLV; these antibodies detected group-specific antigenic determinants of the p15 protein, since reactions were observed with the p15 proteins of both AKR and Moloney viruses. In contrast, antisera prepared in C57BL/6 mice against the AKR leukemia K36 reacted strongly with the p30 protein of MuLV, as well as with p15. Antibodies in the C57BL/6 anti-AKR K36 sera detected group-specific antigenic determinants of the p30 protein; reactions were observed with the C57BL/6 anti-AKR K36 serum and the p30 proteins of both AKR and Moloney viruses. It was concluded that mice do have the capacity to respond immunologically to antigenic determinants of the MuLV p30 protein, although in most circumstances this is not observed.