B-cell activation in the mesenteric lymph nodes of resistant BALB/c mice infected with the murine nematode parasite Trichuris muris

Immune responses in resistant BALB/c mice infected with the murine nematode parasite Trichuris muris were examined. Following the establishment of infection, worm burdens of T. muris were expelled by BALB/c mice by day 21 postinfection (p.i.). Specific immunoglobulin G1 (IgG1) antibodies to T. muris excretory/secretory (E/S) antigens were detected in sera from infected mice, though specific IgG2a antibodies were not observed during infection. Ig-producing cells increased in the mesenteric lymph nodes (MLN) of infected mice on days 7, 14, and 21 p.i., with the greatest increase in numbers of IgG- and IgA-producing cells occurring on day 14. Marked increases in the relative percentages of B220+ and surface Ig+ (sIg+) cells were observed in the MLN of infected mice on days 14 and 21 p.i. Furthermore, cellular expansion of the MLN in infected mice resulted in an increase in the absolute numbers of B220+ and sIg+ cells. The levels of interleukin 2 (IL-2), IL-4, and interferon-gamma (IFN-gamma) detected in the supernatants from concanavalin A-stimulated MLN cells of infected mice were higher than those found in normal mice. Consequently, the expulsion of T. muris in resistant BALB/c mice was concomitant with cytokine production and B-cell activation in the MLN of infected mice. These results suggest the involvement of B-cell responses in protective immunity to T. muris infection.     

Differences in the kinetics of T cell accumulations in C3H/HeN (Bcg-resistant) and C57BL/6 (Bcg-susceptible) mice infected with Mycobacterium paratuberculosis

The accumulation of various T cell subsets in Bcg-susceptible (C57BL/6) and- resistant (C3H/HeN) strains of mice were compared following an intraperitoneal infection with Mycobacterium paratuberculosis. Groups of mice from both strains were killed at 3, 5, 10, 15, 30, and 150 days after infection and lymphocytes were harvested from the peritoneal exudate cells (PEC), spleen, intestinal epithelial lymphocytes (IEL), lamina propria lymphocytes (LPL), Peyer's patches, and mesenteric lymph node (MLN) and labelled with monoclonal antibodies to CD3, CD4, CD8, gamma delta TCR, CD25, and CD44 for flow cytometric analysis. Uninfected C3H/HeN mice had higher proportions of CD4+ cells in the spleen, MLN, LPL, IEL, and Peyer's patches, while uninfected C57BL/6 mice had higher proportions of CD8+ and/or gamma delta T cells. Significant increases in accumulation of CD8+ and gamma delta T cells were detected in the peritoneum and other tissues in both strains of mice after infection. Higher CD4/CD8 ratios were observed in most lymphoid tissues of C3H/HeN mice, while increased proportions of CD8+ and/or gamma delta T cells were present in C57BL/6 mice. These results indicate that significant differences in T cell profiles exist between these two strains of mice, both inherently and in response to infection with M. paratuberculosis. Innately lower levels of CD4+ cells and/or higher percentages of CD8+ and gamma delta T cells may play a role in the increased suspectibility of C57BL/6 mice to infection with M. paratuberculosis.     

Changes in murine jejunal morphology evoked by the bacterial superantigen Staphylococcus aureus enterotoxin B are mediated by CD4+ T cells

Bacterial superantigens (SAgs) are potent T-cell stimuli that have been implicated in the pathophysiology of autoimmune and inflammatory disease. We used Staphylococcus aureus enterotoxin B (SEB) as a model SAg to assess the effects of SAg exposure on gut form and cellularity. BALB/c, SCID (lacking T cells) and T-cell-reconstituted SCID mice were treated with SEB (5 or 100 microg intraperitoneally), and segments of the mid-jejunum were removed 4, 12, or 48 h later and processed for histochemical or immunocytochemical analysis of gut morphology and major histocompatibility complex class II (MHC II) expression and the enumeration of CD3+ T cells and goblet cells. Control mice received saline only. SEB treatment of BALB/c mice caused a time- and dose-dependent enteropathy that was characterized by reduced villus height, increased crypt depth, and a significant increase in MHC II expression. An increase in the number of CD3+ T cells was observed 48 h after exposure to 100 microg of SEB. Enteric structural alterations were not apparent in SEB-treated SCID mice compared to saline-treated SCID mice. In contrast, SEB challenge of SCID mice reconstituted with a mixed lymphocyte population or purified murine CD4+ T cells resulted in enteric histopathological changes reminiscent of those observed in SEB-treated BALB/c mice. These findings implicate CD4+ T cells in this SEB-induced enteropathy. Our results show that SAg immune activation causes significant changes in jejunal villus-crypt architecture and cellularity that are likely to impact on normal physiological processes. We speculate that the elevated MHC II expression and increased number of T cells could allow for enhanced immune responsiveness to other SAgs or environmental antigens.     

Epirubicin in hepatocellular carcinoma: pharmacokinetics and clinical activity

BACKGROUND: Severe combined immunodeficient (SCID) mice develop Epstein-Barr virus (EBV) containing human lymphoproliferative disease (LPD) tumors when reconstituted with human peripheral blood leukocytes (PBLs) from EBV-seropositive donors, but LPD tumors do not develop in the presence of immunosuppressive agents, such as cyclosporine A or corticosteroids. METHODS: Therefore, LPD development in SCID mice was used as a model to explore the relationship among B cells, T cells, and EBV in vivo. SCID mice were engrafted with PBLs isolated by leukapheresis from a single EBV-seropositive donor. Purified populations of CD3+ lymphocytes (T cells) or CD19+ lymphocytes (B cells) were isolated and engrafted into SCID mice. RESULTS: SCID mice engrafted with purified CD3+ lymphocytes (T cells) or CD19+ lymphocytes (B cells) did not develop LPD. In contrast, mice engrafted with purified B cells developed LPD if they were co-engrafted with purified T cells or if they were inoculated with infectious EBV. CONCLUSIONS: This study confirms the requirement of T cells or active EBV infection in the development of LPD in animals engrafted with B cells latently infected with EBV. A greater understanding of the cellular and viral interactions leading to transformation and malignancy may allow the development of specific interventional therapies for malignancies in the immunosuppressed host.     

Long-lived and transferable tumor immunity in mice after targeted interleukin-2 therapy

A major goal of tumor immunotherapy is the induction of tumor-specific T cell responses that are effective in eradicating disseminated tumor, as well as mounting a persistent tumor-protective immunity. We demonstrate here that a genetically engineered fusion protein consisting of human/mouse chimeric anti-ganglioside GD2 antibody and human interleukin-2 is able to induce eradication of established B78-D14 melanoma metastases in immunocompetent syngeneic C57BL/6J mice. This therapeutic effect is mediated by host immune cells, particularly CD8+ T cells and is associated with the induction of a long-lived immunity preventing tumor growth in the majority of animals when challenged up to four months later with B78-D14 cells. This effect was tumor-specific, since no cross-protection against syngeneic, ganglioside GD2+ EL-4 thymoma cells was observed. Furthermore, this tumor-specific protection can be transmitted horizontally to naive, syngeneic SCID mice by passive transfer of CD8+ T lymphocytes derived from immune animals. These results suggest that antibody-targeted delivery of cytokines provides a means to elicit effective immune responses against established tumors in the immunotherapy of neoplastic disease.     

Cellular dynamics and cytokine responses in BALB/c mice infected with Eimeria papillata during primary and secondary infections

BALB/c mice were infected with the intestinal intracellular parasite Eimeria papillata to characterize lymphocyte responses and cytokine profiles throughout primary and secondary infections. Lymphocytes from the mesenteric lymph node (MLN) and the gastrointestinal tract (GIT) of infected mice were phenotypically analyzed using flow cytometry and immunofluorescence microscopy, respectively. Lymphocytes isolated from the MLN during primary infections of BALB/c mice with E. papillata do not proliferate, compared to day 0 uninfected controls, when stimulated in vitro with conconavalin A and express TH2-type cytokines (interleukin [IL]-4 and IL-10) on day 3 PI followed by the release of TH1-type cytokines (IL-2 and interferon-gamma) during patency. In the small intestine, significantly more T cells and their subsets were observed during primary infection. During secondary infections, IL-2 was the only 1 of the 4 cytokines that was expressed earlier and at higher levels in the MLN when compared to primary infections. In the small intestine, significantly more alphabeta+ and CD8+ T lymphocytes were observed in mice during secondary infection. Oocyst antigens did not induce cellular proliferation at any time point during primary or secondary infections. We conclude that primary oral infection of BALB/c mice with E. papillata is associated with localized immunosuppression that may be mediated, in part, by early TH2-type cytokines. Immunity to secondary infection may be mediated by intestinal alphabeta+ CD8+ T lymphocytes through an IL-2-dependent mechanism.     

Interdisciplinary approach to functional voice disorders: the psychiatrist''s role

The Trichuris muris-mouse model of intestinal helminth infection provides a convenient system to examine the immune mechanisms operating during acute and chronic infection. Particular subsets of helper T lymphocytes (CD4+Th cells) play an important role in regulating infection via the secretion of distinct groups of cytokines. Reciprocal activation of Th cell subsets is associated with either expulsion of the parasites from the intestine (Th2 cells) or chronic infection (Th1 cells). In vivo neutralization experiments using anti-cytokine monoclonal antibodies show that critical cytokines are involved, with interferon-gamma playing an important role in the establishment of chronic trichuriasis and interleukin-4 in expulsion of the parasite from the gut. This model has provided clear evidence of a crucial role for distinct cytokines in mediating host protection against intestinal helminth infection and that manipulation of the immune response through the Th cell-cytokine axis can benefit either the host or the parasite. As such, the T. muris model is poised to generate important new data relevant not only to intestinal helminthiasis but to the wider field of parasite immunity and infection in general.     

Gut-derived intraepithelial lymphocytes induce long term immunity against Toxoplasma gondii

Intraepithelial lymphocytes (IEL) of the intestine represent an important barrier in the prevention of infection against orally acquired pathogens. Adoptive transfer of Ag-primed IEL into a naive host can protect against challenge. Using a murine model, we demonstrate in two genetically distinct mouse strains (C57BL/6 and CBA/J) that protective IEL can be isolated at specific times after oral infection with cysts containing bradyzoites. Adoptive transfer of IEL obtained from the intestine of infected mice at these specific times can provide long term protection, as determined by mortality and cyst number against challenge. The protective IEL appear to be CD8+, TCR-alpha/beta and are at least partially dependent upon the presence of TCR-gamma/delta T cells in the host. Endogenous production of the pivotal cytokine, IFN-gamma, is essential for host immunity. These findings demonstrate that gut-derived IEL represent a potentially important mechanism to provide long term immunity to the host.     

Cytotoxic reactivity of gut lamina propria CD4+ alpha beta T cells in SCID mice with colitis

Polyclonal, mucosa-seeking memory/effector CD4+ T cells containing a large fraction of blasts activated in situ accumulate in the gut lamina propria of severe-combined immunodeficient (SCID) mice developing colitis after CD4+ T cell transplantation. CD4+ T cells isolated from different repopulated lymphoid tissues of transplanted SCID mice proliferate in vitro in the presence of interleukin (IL)-2 + IL-7. CD3 ligation enhances this cytokine-supported proliferation in CD4+ T cells from the spleen and the mesenteric lymph node of transplanted SCID mice; CD3 ligation suppresses the cytokine-supported proliferation in CD4+ T cells from the gut lamina propria in a cell density- and dose-dependent manner. Almost all CD4+ T cells from repopulated lymphoid tissues of transplanted SCID mice express CD95 (Fas) on the cell surface, and a large fraction of CD4+ T cells from the gut lamina propria of transplanted SCID mice express the Fas ligand on the surface. Gut lamina propria CD4+ T cells show Fas-dependent cytotoxicity. A large fraction of gut lamina propria CD4+ T cells that infiltrate the inflamed colon in transplanted SCID mice are activated in situ and many CD4+ T cells are apoptotic. Hence, a large fraction of colitis-inducing CD4+ T cells undergo activation-induced cell death in situ and can damage other cells through Fas-dependent cytotoxicity.     

The inflammatory response to nonfatal Sindbis virus infection of the nervous system is more severe in SJL than in BALB/c mice and is associated with low levels of IL-4 mRNA and high levels of IL-10-producing CD4+ T cells

SJL mice are susceptible to inflammatory autoimmune diseases of the central nervous system (CNS), while BALB/c mice are relatively resistant. To understand differences in immune responses that may contribute to autoimmune neurologic disease, we compared the responses of SJL and BALB/c mice to infection with Sindbis virus, a virus that causes acute nonfatal encephalomyelitis in both strains of mice. Clearance of virus was similar, but SJL mice developed a more intense inflammatory response in the brain and spinal cord and inflammation persisted for several weeks. Analysis of lymphocytes isolated from brains early after infection showed an absence of NK cells in SJL mice, while both strains of mice showed CD4+ and CD8+ T cells. During the second week after infection, CD4+ T cells increased in SJL mice and the proportion of CD8+ T cells decreased, while the opposite pattern was seen in BALB/c mice. Expression of IL-10 mRNA was higher and IL-4 mRNA was lower in the brains of infected SJL than in BALB/c mice, while expression of the mRNAs of IL-6, IL-1beta, TNFalpha, and the Th1 cytokines IL-2, IL-12, and IFN-gamma was similar. Lymphocytes isolated from the CNS of SJL mice produced large amounts of IL-10. CNS lymphocytes from both strains of mice produced IFN-gamma in response to stimulation with Sindbis virus, but not in response to myelin basic protein. These data suggest that IL-10-producing CD4+ T cells are differentially recruited to or regulated within the CNS of SJL mice compared with BALB/c mice infected with Sindbis virus, a characteristic that may be related to low levels of IL-4, and is likely to be involved in susceptibility of SJL mice to CNS inflammatory diseases.     

Immunopathology of herpetic stromal keratitis: discordance in CD4+ T cell function between euthymic host and reconstituted SCID recipients

Infection of the mouse cornea with herpes simplex virus (HSV) results in an immunopathologic disease of the eye termed herpetic stromal keratitis (HSK), in which the principal orchestrator is the CD4+ T cell. The mouse genotype largely determines susceptibility or resistance to HSK. BALB/c mice (H2dIgh-1a) are susceptible, while its congenic C.B-17 strain (H2dIgh-1b), which differs only in the Ig heavy chain locus, is resistant to HSK. As the magnitude and duration of viral replication as well as anti-HSV immune responses were similar in both strains, it was determined whether resistance was due to failure of CD4+ T cells to organize the immunopathologic reaction. Adoptive transfer of HSV-primed or naive CD4+ T cells from resistant C.B-17 strain into HSV-infected SCID mice resulted in HSK lesions indistinguishable from those caused by similar transfers of BALB/c CD4+ T cells. Similar results were obtained with transfers of whole T cell populations as well as with unfractionated splenocytes from the resistant mice. These results show that while intact C.B-17 mice exhibit resistance to HSK, they possess potentially pathogenic CD4+ T cells in their repertoire. The data suggest that the HSV-infected SCID mouse provides a proinflammatory microenvironment that overrides regulatory controls and/or cause activation of quiescent cells into aggressive effector T cells that orchestrate HSK.     

Resistance to and recovery from lethal influenza virus infection in B lymphocyte-deficient mice

In the adaptive immune response to most viruses, both the cellular and humoral arms of the immune system play complementary roles in eliminating virus and virus-infected cells and in promoting recovery. To evaluate the relative contribution of CD4+ and CD8+ effector T lymphocytes in virus clearance and recovery, we have examined the host response to lethal type A influenza virus infection in B lymphocyte-deficient mice with a targeted disruption in the immunoglobulin mu heavy chain. Our results indicate that naive B cell-deficient mice have a 50- 100-fold greater susceptibility to lethal type A influenza virus infection than do wild type mice. However, after priming with sublethal doses of influenza, immune B cell-deficient animals show an enhanced resistance to lethal virus infection. This finding indicates that an antibody-independent immune-mediated antiviral mechanism accounts for the increased resistance to lethal virus challenge. To assess the contribution of influenza-specific CD4+ and CD8+ effector T cells in this process, defined clonal populations of influenza-specific CD4+ and CD8+ effector T cells were adoptively transferred into lethally infected B cell-deficient mice. Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection. These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals. The potential implications of these results for vaccination against human influenza infection are discussed.     

Genetic immunization with glycoprotein 63 cDNA results in a helper T cell type 1 immune response and protection in a murine model of leishmaniasis

Genetic immunization is a promising gene therapy approach for the prevention and treatment of infectious disease. Plasmid DNA expressing genes of pathogens is directly introduced into host cells and specific cell-mediated and/or humoral immune responses are elicited against the encoded protein. Leishmaniasis is a significant world-wide health problem for which no vaccine exists. In susceptible animals, such as BALB/c mice, protection from leishmaniasis requires induction of a Thl immune response. In this study, cell-mediated immunity to Leishmania major (L. major) was induced by injecting BALB/c mice intradermally with plasmid DNA expressing the conserved L. major cell surface glycoprotein gp63 (gp63-pcDNA-3). CD4 T lymphocytes from gp63-pcDNA-3-immunized mice proliferated and produced IFN-gamma (but not IL-4) when stimulated in vitro with freeze-thawed parasites, consistent with a Th1 immune response. In contrast, lymphocyte proliferation in animals immunized with freeze-thawed parasites was associated with IL-4 (but not IFN-gamma) production, suggesting a nonprotective Th2 response. Challenge studies revealed that gp63-pcDNA-3 vaccination protected 30% of susceptible mice (21 of 70) from Leishmania infection while neither gp63 protein (0 of 20) nor freeze-thawed parasite vaccines (0 of 50) were efficacious. Dendritic cells derived from skin of gp63-pcDNA-3-injected mice also immunized naive recipients and protected them from leishmaniasis. We conclude that gp63-pcDNA-3 genetic vaccination results in a CD4-dependent Th1 immune response that correlates with protection from disease, and suggest that skin-derived dendritic cells are involved in priming this response.     

Consumer protection in managed care: finding the balance

CD8+ cytotoxic T lymphocytes (CTL) have an established role in anti-viral immunity, but whether CTL function efficiently in the brain remains unclear. In particular, virus-infected neurons, which express only low levels of MHC class I antigens and are resistant to the induction of apoptosis, could constitute a relatively intractable CTL target. We have used immune lymphocytes adoptively transferred into the CSF to protect naive mice against an intracerebral infection with influenza A/WSN, a virus that infects neurons in the brain parenchyma and causes a lethal encephalitis. After in vitro restimulation, heterotypically immune spleen cells protected against A/WSN encephalitis in an H-2-restricted, CD8-dependent, CD4-independent manner. Adoptively transferred CTL clones were also protective. Homotypically immune spleen cells additionally mediated CD8-independent, H-2-unrestricted protection, probably due to the generation of A/WSN-specific plasma cells from memory B cells during in vitro restimulation. Thus after in vitro restimulation, either CTL or B cells adoptively transferred into the CSF protected against an acutely lethal intracerebral virus infection.     

T lymphocyte roles during Eimeria acervulina and Eimeria tenella infections

This study evaluated the effects of selective depletion of T lymphocytes on Eimeria infections in chickens. Cell depletions were initiated in day- or week-old Hyline SC strain chickens using intra-peritoneal injections of monoclonal antibodies to CD4, CD8, or T cell receptor (TCR) alpha/beta. Control chickens received injections of irrelevant monoclonal antibody or phosphate buffered saline (PBS). Following the establishment of cell depletion, chickens were infected orally with E. acervulina or E. tenella, 1 x 10(4) oocysts for primary infections and 2 x 10(5) oocysts for secondary infections. Chickens treated with anti CD4 monoclonal antibody produced significantly more oocysts than controls following primary E. tenella but not E. acervulina infections. Development of resistance to challenge infection was unaffected. These results suggest that CD4+ lymphocytes are important in controlling primary infection with E. tenella. Chickens treated with anti-CD8 or anti-TCR alpha/beta monoclonal antibodies produced significantly fewer oocysts than controls following primary infection but significantly more oocysts than controls following secondary infection with both E. tenella and E. acervulina. Additionally, anti-CD8 treatment abrogated resistance to challenge infection. CD8-depleted chickens may exhibit decreased oocyst production following primary infection due to a lack of CD8+ lymphocytes to serve as transporting cells for sporozoites. The abrogation of resistance to secondary infection in CD8- and TCR alpha/beta-depleted chickens suggests that these cells are necessary for the development of protective immunity to coccidia.     

Cooperation of B cells and T cells is required for survival of mice infected with vesicular stomatitis virus

To define the role of T cells and B cells in resistance to vesicular stomatitis virus (VSV) infection, knockout mice with different specific immune defects on an identical background were infected i.v. and the outcome of infection was compared; in this way a more complete picture of the relative importance of various host defence mechanisms could be obtained. Compared to T and B cell-deficient SCID mice which all succumbed from encephalitis within 5-9 days of infection, T cell-deficient nude mice generally lived longer, but within a period of approximately 1 month after challenge all died. In contrast, B cell-deficient mice were highly susceptible even to low doses of virus and mortality could be prevented by transfer of naive B cells prior to challenge as well as by immune serum given after challenge. Analysis of MHC class I- and class II-deficient mice revealed that CD8+ T cells could exert some antiviral activity, but CD4+ T cells sufficed for survival and were required for optimal resistance. Consistent with this it was found that in nude mice a lethal outcome could be prevented by transfer of CD8-depleted cells from B cell-deficient mice. Thus our results clearly demonstrate that while antibodies are pivotal for survival in the early phase of VSV infection, T cells are required for long-term survival, with CD4+ T cells being more effective in controlling this infection than CD8+ T cells.     

Role of T lymphocyte subsets in immunity to spotted fever group Rickettsiae

To evaluate the roles of CD4 and CD8 T lymphocytes in immunity to disseminated endothelial infection with Rickettsia conorii (Malish 7 strain), these T cell subsets were depleted or adoptively transferred into subsequently infected C3H/HeN mice. CD4 T lymphocyte-depleted and sham-depleted mice underwent a similar course of illness with a sublethal rickettsial dose, cleared the infection by day 10, and recovered on days 10 to 11. In contrast, mice depleted of CD8 lymphocytes or CD4 and CD8 lymphocytes died or remained persistently infected through day 15 with the ordinarily sublethal dose. Endothelium was the major site of rickettsial persistence, including sites in the vital organs, brain, and lungs of CD8 lymphocyte-depleted mice. In nondepleted animals, CD8 T lymphocytes were observed in apposition to endothelial cells on day 10 at the time of rickettsial clearance. Adoptive transfer of immune CD4 or CD8 T lymphocytes protected mice against a lethal dose of R. conorii in the disseminated endothelial target model. Nonimmune CD4 or CD8 lymphocytes and immune lymphocytes that had passed through columns that depleted both CD4 and CD8 lymphocytes failed to protect mice against R. conorii. These studies represent the first analysis of the role of T lymphocyte subsets in immunity to spotted fever group rickettsiae and the first demonstration that clearance of spotted fever group rickettsiae from endothelial cells requires immune CD8 T lymphocytes.     

Avian gut-associated immune system: implication in coccidial vaccine development

Host responses to coccidia are complex and involve both humoral and cellular immune mechanisms. Convincing evidence exists for a major role of cell-mediated immunity in anticoccidial resistance. With an increasing need for the development of coccidial vaccine, understanding of the intestinal immune system is crucial. To provide increased insight into the immune mechanisms involving mucosal immune response to coccidia, cellular events involved in the maturation of intestinal immune system were studied. Postnatal development of various T lymphocyte subpopulations expressing CD3, CD8, CD4, and antigen-specific T cell receptor (TCR) heterodimers expressing gamma delta (TCR1) or alpha beta (TCR2) was investigated in chickens. Intraepithelial lymphocytes (IEL) expressing the CD8 antigen increased gradually following hatching and subsequently declined with age. The CD4+ cells represented a minor subpopulation among the IEL. The ratios of IEL T cells expressing gamma delta (TCR1) or alpha beta (TCR2) in the intraepithelium of chickens gradually increased after hatching. These results indicate maturational changes of intestinal immune system that should be considered in the development of vaccine against coccidia.     

Stimulation of protective CD8+ T lymphocytes by vaccination with nonliving bacteria

Infectious diseases caused by intracellular microbes are responsible for major health problems, and satisfactory control will ultimately depend on efficient vaccination strategies. The general assumption is that activation of protective immune responses against intracellular microbes dominated by CD8+ T cells are achieved only by live vaccines. In contrast, we here demonstrate stimulation of protective immunity in mice against the intracellular pathogen Listeria monocytogenes by vaccination with heat-killed listeriae. Vaccine-induced immunity comprised cytolytic and interferon gamma-producing CD8+ T lymphocytes. CD8+ T cells from vaccinated donor mice transferred protection against listeriosis. Moreover, vaccination with heat-killed listeriae induced production in CD4+ T-cell-deficient, H2-A beta gene-disrupted mutant mice. We conclude that antigens from killed listeriae are introduced into the major histocompatibility complex class I pathway and thus are recognized by CD8+ T cells. The practicability of killed vaccines against human infectious diseases therefore should be reevaluated.     

Mucosal immunity to herpes simplex virus type 2 infection in the mouse vagina is impaired by in vivo depletion of T lymphocytes

Intravaginal (IVAG) inoculation of wild-type herpes simplex virus type 2 (HSV-2) in mice causes epithelial infection followed by lethal neurological illness, while IVAG inoculation of attenuated HSV-2 causes epithelial infection followed by development of protective immunity against subsequent IVAG challenge with wild-type virus. The role of T cells in this immunity was studied by in vivo depletion of these cells with monoclonal antibodies. Three groups of mice were used for each experiment: nonimmune/challenged mice, immune/challenged mice, and immune depleted mice [immune mice depleted of a T-cell subset(s) shortly before challenge with HSV-2]. Mice were assessed for epithelial infection 24 h after challenge, virus protein in the vaginal lumen 3 days after challenge, and neurological illness 8 to 14 days after challenge. Monoclonal antibodies to CD4, CD8, or Thy-1 markedly reduced T cells in blood, spleen, and vagina, but major histocompatibility complex class II antigens were still partially upregulated in the vaginal epithelium after virus challenge, indicating that virus-specific memory T-cell function was not entirely eliminated from the vagina. Nevertheless, immune mice depleted of CD4+ and CD8+ T cells, Thy-1+ T cells, or CD8+ T cells alone had greater viral infection in the vaginal epithelium than nondepleted immune mice, indicating that T cells contribute to immunity against vaginal HSV-2 infection. All immune depleted mice retained substantial immunity to epithelial infection and were immune to neurological illness, suggesting that other immune mechanisms such as virus-specific antibody may also contribute to immunity.