Abstract
IntroductionNatalizumab blocks α4-integrins and is a prototypic agent for a series of anti-inflammatory drugs that impair trafficking of immune cells into the CNS. However, modulation of the access of immune cells to the CNS is associated with impaired immune surveillance and detrimental viral infections of the CNS. Here, we explored the potency of cellular immune responses within the CNS to protect against viral encephalitis in mice with T cell conditional disruption of VLA-4 integrin (α4β1) expression.ResultsWhile VLA-4 expression in virus specific Th1 cells is non-redundant for their ability to access the CNS, α4-integrin deficient Th17 cells enter the CNS compartment and generate an inflammatory milieu upon intrathecal vaccinia virus (VV) infection. However, in contrast to Th1 cells that can adopt direct cytotoxic properties, Th17 cells fail to clear the virus due to insufficient Eomes induced perforin-1 expression.ConclusionThe quality of the intrathecal cellular antiviral response under conditions of impaired VLA-4 function jeopardizes host protection. Our functional in vivo data extend our mechanistic understanding of anti-viral immunity in the CNS and help to estimate the risk potential of upcoming therapeutic agents that target the trafficking of immune cells into distinct anatomical compartments.
Highlights
Natalizumab blocks α4-integrins and is a prototypic agent for a series of anti-inflammatory drugs that impair trafficking of immune cells into the CNS
Intrathecal vaccinia virus (VV) infection causes lethal encephalitis To establish a model of viral encephalitis, female C57BL/6 mice were injected intrathecally with VV by suboccipital puncture of the cisterna magna
While high titers of VV were measured in the CNS, virus was not detected in the ovaries of intrathecally infected mice (Figure 1B) indicating that intrathecal injection of VV led to a compartmentalized infection within the CNS without systemic dissemination
Summary
Natalizumab blocks α4-integrins and is a prototypic agent for a series of anti-inflammatory drugs that impair trafficking of immune cells into the CNS. We explored the potency of cellular immune responses within the CNS to protect against viral encephalitis in mice with T cell conditional disruption of VLA-4 integrin (α4β1) expression. For many years integrin targeted blocking of T helper cell trafficking into the CNS has appeared to be an attractive approach to treat immunopathology in MS [2]. Monoclonal antibodies (natalizumab) to the α4 subunit of the integrin VLA-4 (α4β1 heterodimer) were successfully used to prevent the influx of immune cells into the CNS and to treat CNS autoimmunity [3]. Blockade of VLA-4 is more efficient in preventing the recruitment of Th1 cells than of Th17 cells into the CNS parenchyma
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