Lymphocyte activation gene-3 (LAG-3) is a CD4-related, activation-induced cell surface molecule that binds to MHC class II with high affinity. In this study, we used four experimental systems to reevaluate previous suggestions that LAG-3−/− mice had no T cell defect. First, LAG-3−/− T cells exhibited a delay in cell cycle arrest following in vivo stimulation with the superantigen staphylococcal enterotoxin B resulting in increased T cell expansion and splenomegaly. Second, increased T cell expansion was also observed in adoptive recipients of LAG-3−/− OT-II TCR transgenic T cells following in vivo Ag stimulation. Third, infection of LAG-3−/− mice with Sendai virus resulted in increased numbers of memory CD4+ and CD8+ T cells. Fourth, CD4+ T cells exhibited a delayed expansion in LAG-3−/− mice infected with murine gammaherpesvirus. In summary, these data suggest that LAG-3 negatively regulates T cell expansion and controls the size of the memory T cell pool.
The γ-herpesviruses are oncogenic B cell lymphotrophic viruses that establish life-long latency in the host. Murine γ-herpesvirus 68 (MHV-68) infection of mice represents a unique system for analyzing γ-herpesvirus latency in splenic B cells at different stages of infection. After intranasal infection with MHV-68 we analyzed the establishment of latency 14 days after infection, and the maintenance of latency 3 months after infection in different purified subpopulations of B cells in the spleen. The data show that MHV-68 latency is mainly established in germinal center B cells and that long-term latency is preferentially maintained in two different subsets of isotype-switched B cells, germinal center and memory B cells. Cell cycle analysis indicates that MHV-68 is located in both cycling and resting isotype-switched B cells. Analysis of viral gene expression showed that both lytic and latent viral transcripts were differentially expressed in germinal center and memory B cells during long-term latency. Together, these observations suggested that γ-herpesviruses exploit the B cell life cycle in the spleen.
The human γ-herpesviruses, EBV and Kaposi’s sarcoma-associated herpesvirus, establish life-long latency and can reactivate in immunocompromised individuals. T cells play an important role in controlling persistent EBV infection, whereas a role for humoral immunity is less clear. The murine γ-herpesvirus-68 has biological and structural similarities to the human γ-herpesviruses, and provides an important in vivo experimental model for dissecting mechanisms of immune control. In the current studies, CD28−/− mice were used to address the role of Abs in control of persistent murine γ-herpesvirus-68 infection. Lytic infection was controlled in the lungs of CD28−/− mice, and latency was maintained in B cells at normal frequencies. Although class-switched virus-specific Abs were initially generated in the absence of germinal centers, titers and viral neutralizing activity rapidly waned. T cell depletion in CD28−/− mice with compromised Ab responses, but not in control mice with intact Ab responses, resulted in significant recrudescence from latency, both in the spleen and the lung. Recrudescence could be prevented by passive transfer of immune serum. These data directly demonstrate an important contribution of humoral immunity to control of γ-herpesvirus latency, and have significant implications for clinical intervention.
Zika virus (ZIKV) infection during human pregnancy may cause diverse and serious congenital defects in the developing fetus. Previous efforts to generate animal models of human ZIKV infection and clinical symptoms often involved manipulating mice to impair their Type I interferon (IFN) signaling, thereby allowing enhanced infection and vertical transmission of virus to the embryo. Here, we show that even pregnant mice competent to generate Type I IFN responses that can limit ZIKV infection nonetheless develop profound placental pathology and high frequency of fetal demise. We consistently found that maternal ZIKV exposure led to placental pathology and that ZIKV RNA levels measured in maternal, placental or embryonic tissues were not predictive of the pathological effects seen in the embryos. Placental pathology included trophoblast hyperplasia in the labyrinth, trophoblast giant cell necrosis in the junctional zone, and loss of embryonic vessels. Our findings suggest that, in this context of limited infection, placental pathology rather than embryonic/fetal viral infection may be a stronger contributor to adverse pregnancy outcomes in mice. Our finding demonstrates that in immunocompetent mice, direct viral infection of the embryo is not essential for fetal demise. Our immunologically unmanipulated pregnancy mouse model provides a consistent and easily measurable congenital abnormality readout to assess fetal outcome, and may serve as an additional model to test prophylactic and therapeutic interventions to protect the fetus during pregnancy, and for studying the mechanisms of ZIKV congenital immunopathogenesis.
Infectious bursal disease virus (IBDV) is an avian lymphotropic virus that causes immunosuppression.When specific-pathogen-free chickens were exposed to a pathogenic strain of IBDV (IM), the virus rapidly destroyed B cells in the bursa of Fabricius. Extensive viral replication was accompanied by an infiltration of T cells in the bursa. We studied the characteristics of intrabursal T lymphocytes in IBDV-infected chickens and examined whether T cells were involved in virus clearance. Flow cytometric analysis of single-cell suspensions of the bursal tissue revealed that T cells were first detectable at 4 days postinoculation (p.i.). At 7 days p.i., 65% of bursal cells were T cells and 7% were B cells. After virus infection, the numbers of bursal T cells expressing activation markers Ia and CD25 were significantly increased (P < 0.03). In addition, IBDV-induced bursal T cells produced elevated levels of interleukin-6-like factor and nitric oxide-inducing factor in vitro. Spleen and bursal cells of IBDV-infected chickens had upregulated gamma interferon gene expression in comparison with virus-free chickens. In IBDV-infected chickens, bursal T cells proliferated in vitro upon stimulation with purified IBDV in a dose-dependent manner (P < 0.02), whereas virus-specific T-cell expansion was not detected in the spleen. Cyclosporin A treatment, which reduced the number of circulating T cells and compromised T-cell mitogenesis, increased viral burden in the bursae of IBDV-infected chickens. The results suggest that intrabursal T cells and T-cell-mediated responses may be important in viral clearance and promoting recovery from infection.Infectious bursal disease virus (IBDV), an avian B-lymphotropic virus, causes an acute productive infection in actively dividing immunoglobulin M-expressing (IgM ϩ ) B cells (16,28). The bursa is the principal reservoir of virus replication, and peak virus titers in the bursa can be detected between 3 to 5 days after IBDV infection (20,38). The bursa of Fabricius is a unique, primary lymphoid organ in avian species, where B lymphocytes maturate and differentiate (14). The bursal follicles consist of B lymphocytes (85 to 95%), T cells (Ͻ4%), and other nonlymphoid cells (4,10,21,31). In the bursae of chickens infected with IBDV, productive viral replication is often associated with necrosis, apoptosis of lymphoid cells, inflammatory change, atrophy, and hemorrhages (16,25,38,42). Chickens infected with IBDV experience suppression in both humoral (8,13,32,39) and cellular (5, 23, 32) immunity. Humoral immunosuppression appears to be associated with IBDV-induced B-cell destruction, while the mechanism of cellular immunosuppression is largely elusive.Because viral replication is self-limiting, birds recover from the pathogenic effects of the virus. After the acute phase of the infection subsides, the bursal follicles become repopulated with B cells and immune competence is reestablished (24). The mechanisms that limit virus replication and promote recovery are not known and may involve virus-spe...
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