Influence of Host Genes on the Outcome of Murine Lymphocytic Choriomeningitis Virus Infection

Adhesive interactions are crucial to cell migration into inflammatory sites. Using murine lymphocytic choriomeningitis virus as an Ag model system, we have investigated expression and function of collagen-binding integrins, α1β1 and α2β1, on activated and memory T cells. Using this system and MHC tetramers to define Ag-specific T cells, we demonstrate that contrary to being VLAs, expression of α1β1 and α2β1 can be rapidly induced on acutely activated T cells, that expression of α1β1 remains elevated on memory T cells, and that expression of α1β1 parallels that of viral-specific effector CD8+ T cells (defined by tetramer and IFN-γ staining). In an adoptive transfer model, mAb-mediated blockade of these integrins on activated effector and memory T cells inhibited Ag-specific delayed-type hypersensitivity responses; similar decreased responses were seen upon transfer of α1-deficient activated/memory T cells. Thus, expression of α1β1 and α2β1 integrins on activated T cells is directly functionally important for generation of inflammatory responses within tissues. Finally, the inhibitory effect of α1β1 blockade on the delayed-type hypersensitivity response could be bypassed by direct injection of Ag-specific T cells to inflammatory sites, demonstrating for the first time in vivo that collagen-binding integrins are involved in leukocyte migration into tissues.

“…An i.v. injection of LCMV into immunocompetent mice normally results in transient immunizing infection (18,26,28). For infection with VSV, mice were inoculated with 10 6 PFU i.v.…”

Section: Infectionsmentioning

confidence: 99%

Expression and Functional Importance of Collagen-Binding Integrins, α1β1 and α2β1, on Virus-Activated T Cells

Andreasen¹,

Thomsen²,

Koteliansky

et al. 2003

“…infection of mice, 4800 PFU of LCMV in a volume of 0.3 ml was used. Inoculation of immunocompetent mice by this route is followed by transient, immunizing infection (19,28). VSV of the Indiana strain, originally provided by K. Berg of this institute, was produced, stored, and quantified as described previously (29).…”

Section: Virus Infectionmentioning

confidence: 99%

Role of CD40 Ligand and CD28 in Induction and Maintenance of Antiviral CD8+ Effector T Cell Responses

Andreasen

Christensen

Marker

et al. 2000

112

130

The primary aim of this report was to evaluate the immune responses of CD40 ligand-deficient (CD40L−/−) mice infected with two viruses known to differ markedly in their capacity to replicate in the host. Lymphocytic choriomeningitis virus (LCMV) is a natural mouse pathogen that replicates widely and extensively, whereas vesicular stomatitis virus (VSV) spreads poorly. We found that the primary response of CD40L−/− mice toward VSV is significantly impaired; proliferation of both CD4+ and CD8+ cells is reduced 2- to 3-fold, few CD8+ cells acquire an activated phenotype, and little functional activity is induced. Very similar results were obtained in VSV-infected, CD28-deficient mice. In contrast, neither CD40L nor CD28 was required for induction of a primary CD8+ response toward LCMV. Surprisingly, lack of CD4+ T cells had no impact on the primary immune response toward any of the viruses, even though the CD40 ligand dependence demonstrated for VSV would be expected to be associated with CD4 dependence. Upon coinfection of VSV-infected mice with LCMV, the requirement for CD40 ligand (but not CD28) could be partially bypassed, as evidenced by a 3-fold increase in the frequency of VSV-specific CD8+ T cells on day 6 postinfection. Finally, despite the fact that the primary LCMV-specific CD8+ response is virtually unimpaired in CD40L−/− mice, their capacity to maintain CD8+ effector activity and to permanently control the infection is significantly reduced. Thus, our results demonstrate that the importance of CD40/CD40L interaction for activation of CD8+ T cells varies between viruses and over time.

“…Together, these findings suggest that although T cell-dependent IFN-␥ production is important, it is not the only mechanism through which viruses may prime for TNF-␣ production. IFN-␣␤ is a likely candidate in this respect, because most viral infections including LCMV and VSV are known to induce substantial production of IFN-␣␤ (21)(22)(23)(24)(25). In virus-infected immunocompetent mice, production of IFN-␣␤ generally reaches peak levels 1-3 days post infection (p.i.…”

Section: Viral Infection Causes Rapid Sensitization Tomentioning

confidence: 99%

Viral Infection Causes Rapid Sensitization to Lipopolysaccharide: Central Role of IFN-αβ

Nansen

Thomsen

2001

LPS is the major active agent in the pathogenesis of Gram-negative septic shock. In this report we have studied the influence of concurrent viral infection on the outcome of LPS-induced shock. We find that infection with vesicular stomatitis virus sensitizes mice to LPS at an early time point following infection. Treatment of mice with the chemical IFN inducer, polyinosinic:polycytidylic acid, has a similar effect. This hypersensitivity to LPS correlated with hyperproduction of TNF-α in vivo. The cellular and molecular mechanisms underlying this phenomenon were investigated using Ab-depleted and gene-targeted mice. Our results revealed that while NK cell depletion and elimination of IFN-γ partially protected against the sensitizing effects of vesicular stomatitis virus and polyinosinic:polycytidylic acid, the most striking effect was observed in IFN-αβR-deficient mice. Thus hyperproduction of TNF-α was completely abrogated in IFN-αβR-deficient mice, indicating that the principal mechanism underlying rapid virus-induced sensitization to LPS is an IFN-αβ-mediated priming of mice for an augmented production of TNF-α in response to LPS. This conclusion was further supported by the finding that pretreatment of mice with rIFN-αβ mimicked the effect of viral infection. In conclusion, our results reveal a previously unrecognized proinflammatory effect of IFN-αβ and point to a new pathway through which viral infection may influence the outcome of concurrent bacterial infection.