IFN-γ-inducible protein 10 (IP-10, CXCL10), a chemokine secreted from cells stimulated with type I and II IFNs and LPS, is a chemoattractant for activated T cells. Expression of IP-10 is seen in many Th1-type inflammatory diseases, where it is thought to play an important role in recruiting activated T cells into sites of tissue inflammation. To determine the in vivo function of IP-10, we constructed an IP-10-deficient mouse (IP-10−/−) by targeted gene disruption. Immunological analysis revealed that IP-10−/− mice had impaired T cell responses. T cell proliferation to allogeneic and antigenic stimulation and IFN-γ secretion in response to antigenic challenge were impaired in IP-10−/− mice. In addition, IP-10−/− mice exhibited an impaired contact hypersensitivity response, characterized by decreased ear swelling and reduced inflammatory cell infiltrates. T cells recovered from draining lymph nodes also had a decreased proliferative response to Ag restimulation. Furthermore, IP-10−/− mice infected with a neurotropic mouse hepatitis virus had an impaired ability to control viral replication in the brain. This was associated with decreased recruitment of CD4+ and CD8+ lymphocytes into the brain, reduced levels of IFN-γ and the IFN-γ-induced chemokines monokine induced by IFN-γ (Mig, CXCL9) and IFN-inducible T cell α chemoattractant (I-TAC, CXCL11) in the brain, decreased numbers of virus-specific IFN-γ-secreting CD8+ cells in the spleen, and reduced levels of demyelination in the CNS. Taken together, our data suggest a role for IP-10 in both effector T cell generation and trafficking in vivo.
Chronic expression of CXC chemokine ligand 10 (CXCL10) in the central nervous system (CNS) following infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) is associated with an immune-mediated demyelinating disease. Treatment of mice with anti-CXCL10 neutralizing antibody results in limited CD4+ T cell infiltration into the CNS accompanied by a reduction in white matter damage. The current study determines the antigen-specificity of the T lymphocytes present during chronic disease and evaluates how blocking CXCL10 signaling affects retention of virusspecific T cells within the CNS. CXCL10 neutralization selectively reduced accumulation and/or retention of virus-specific CD4+ T cells, yet exhibited limited effect on virus-specific CD8+ T cells. The response of CXCL10 neutralization on virus-specific T cell subsets is not due to differential expression of the CXCL10 receptor CXCR3 on T cells as there was no appreciable difference in receptor expression on virus-specific T cells during either acute or chronic disease. These findings emphasize the importance of virus-specific CD4+ T cells in amplifying demyelination in JHMVinfected mice. In addition, differential signals are required for trafficking and retention of virusspecific CD4+ and CD8+ T cells during chronic demyelination in JHMV-infected mice.
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