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.

IFN-γ-inducible protein 10/CXCL10 is a chemokine associated with type 1 T cell responses, regulating the migration of activated T cells through binding to the CXCR3 receptor. Expression of both CXCL10 and CXCR3 are observed during immunopathological diseases of the CNS, and this receptor/ligand pair is thought to play a central role in regulating T cell-mediated inflammation in this organ site. In this report, we investigated the role of CXCL10 in regulating CD8+ T cell-mediated inflammation in the virus-infected brain. This was done through analysis of CXCL10-deficient mice infected intracerebrally with lymphocytic choriomeningitis virus, which in normal immunocompetent mice induces a fatal CD8+ T cell-mediated meningoencephalitis. We found that a normal antiviral CD8+ T cell response was generated in CXCL10-deficient mice, and that lack of CXCL10 had no influence on the accumulation of mononuclear cells in the cerebrospinal fluid. However, analysis of the susceptibility of CXCL10-deficient mice to lymphocytic choriomeningitis virus-induced meningitis revealed that these mice just like CXCR3-deficient mice were partially resistant to this disease, whereas wild-type mice invariably died. Furthermore, despite marked up-regulation of the two remaining CXCR3 ligands: CXCL9 and 11, we found a reduced accumulation of CD8+ T cells in the brain parenchyma around the time point when wild-type mice succumb as a result of CD8+ T cell-mediated inflammation. Thus, taken together these results indicate a central role for CXCL10 in regulating the accumulation of effector T cells at sites of CNS inflammation, with no apparent compensatory effect of other CXCR3 ligands.

T-cells play an important role in controlling viral

Trichloroethylene is an animal carcinogen with limited evidence of carcinogenicity in humans. Cancer incidence between 1968 and 1997 was evaluated in a cohort of 40,049 blue-collar workers in 347 Danish companies with documented trichloroethylene use. Standardized incidence ratios for total cancer were 1.1 (95% confidence interval (CI): 1.04, 1.12) in men and 1.2 (95% CI: 1.14, 1.33) in women. For non-Hodgkin's lymphoma and renal cell carcinoma, the overall standardized incidence ratios were 1.2 (95% CI: 1.0, 1.5) and 1.2 (95% CI: 0.9, 1.5), respectively; standardized incidence ratios increased with duration of employment, and elevated standardized incidence ratios were limited to workers first employed before 1980 for non-Hodgkin's lymphoma and before 1970 for renal cell carcinoma. The standardized incidence ratio for esophageal adenocarcinoma was 1.8 (95% CI: 1.2, 2.7); the standardized incidence ratio was higher in companies with the highest probability of trichloroethylene exposure. In a subcohort of 14,360 presumably highly exposed workers, the standardized incidence ratios for non-Hodgkin's lymphoma, renal cell carcinoma, and esophageal adenocarcinoma were 1.5 (95% CI: 1.2, 2.0), 1.4 (95% CI: 1.0, 1.8), and 1.7 (95% CI: 0.9, 2.9), respectively. The present results and those of previous studies suggest that occupational exposure to trichloroethylene at past higher levels may be associated with elevated risk for non-Hodgkin's lymphoma. Associations between trichloroethylene exposure and other cancers are less consistent.

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