Expression of Mig (Monokine Induced by Interferon-γ) Is Important in T Lymphocyte Recruitment and Host Defense Following Viral Infection of the Central Nervous System

Abstract

Induction of a Th1 immune response against viral infection of the CNS is important in contributing to viral clearance. The present studies demonstrate a role for the T cell chemoattractant chemokine Mig (monokine induced by IFN-γ) in contributing to a Th1 response against mouse hepatitis virus infection of the CNS. Analysis of the kinetics of Mig expression revealed mRNA transcripts present at days 7 and 12 postinfection (p.i.) but not early (day 2) or late (day 35) in the infection. To determine functional significance, mouse hepatitis virus-infected mice were treated with anti-Mig antisera, and the severity of disease was evaluated. Such treatment resulted in a marked increase in mortality that correlated with a >3 log increase in viral burden within the brains as compared with control mice treated with normal rabbit serum. Anti-Mig-treated mice displayed a significant decrease (p < 0.005) in CD4+ and CD8+ T cell recruitment into the CNS as compared with normal rabbit serum-treated mice. In addition, anti-Mig treatment resulted in a significant decrease (p < 0.05) in levels of IFN-γ and IFN-β that coincided with increased (p < 0.02) expression of the anti-inflammatory Th2 cytokine IL-10 within the CNS. Collectively, these data indicate that Mig is important in contributing to host defense by promoting a protective Th1 response against viral infection of the CNS.

Differential roles for CXCR3 in CD4+ and CD8+ T cell trafficking following viral infection of the CNS

“…Sham-infected mice did not exhibit expression of any of the chemokines evaluated. As previous studies from our lab indicated that CXCL9 and CXCL10 attract T cells into the CNS of MHV-infected mice [18,23], CXCR3 expression on T cells was determined. CXCR3 transcripts were present within the brain at 7, 21 and 35 days p.i., correlating with the time that T cells enter the CNS (Fig.…”

“…2C). Although only minor differences in mortality and viral titer were observed, CXCR3 ligands are still important for T cell trafficking, so CD4 + and CD8 + T cell accumulation within the CNS was measured following CXCR3 neutralization [18,19,23]. CD4 + T cell accumulation within the brains of mice treated with anti-CXCR3 was reduced by 69% (p 0.03) at day 7 p.i.…”

“…Studies from our laboratory have clearly demonstrated important roles for CXCR3 ligands during both acute and chronic MHV infection of C57BL/6 mice [18,19,23]. Antibody neutralization of CXCL9 or CXCL10 during acute infection resulted in increased mortality, delayed viral clearance and reduced T cell infiltration into the CNS, indicating that these chemokines are essential components of host defense following viral infection of the CNS [18,23]. In addition, the contribution of these chemokines during the chronic phase of MHV-induced CNS disease was evaluated.…”

“…During both acute and chronic MHV infection, chemokines and chemokine receptors are expressed within the CNS, influencing host defense as well as disease by regulating inflammation within the CNS [9,14,[18][19][20][21][22][23]. Studies from our laboratory have clearly demonstrated important roles for CXCR3 ligands during both acute and chronic MHV infection of C57BL/6 mice [18,19,23].…”

CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection

“…Both CXCL9 and CXCL10 are expressed or upregulated in the cornea and TG in response to corneal infection with HSV-1 [12]. Since T cells are recruited to the inflammatory site during acute ocular HSV-1 infection [4][5][6][7] and CXCL9 and CXCL10 are associated with the recruitment of activated T cells during inflammatory processes [19][20][21][22][23][24], questions remain as to the temporal nature of expression, redundancy in recruitment of T cells, and the impact of expression on the production of other cytokines and chemokines in the inflamed tissue following infection. To address these questions, mice deficient in CXCL9 (CXCL9−/−) or CXCL10 (CXCL10−/−) were compared to wild type (WT) controls for resistance to infection and the local host immune response following placement of the virus onto the cornea.…”