Rotarod performance (B), brain-infiltrating CTL quantities (C and D), perisomatic bouton density in the DCN (E), and the density of cerebellar P-STAT1+ neurons (F) were analyzed at the peak of disease (day 10 after challenge)

Rotarod performance (B), brain-infiltrating CTL quantities (C and D), perisomatic bouton density in the DCN (E), and the density of cerebellar P-STAT1+ neurons (F) were analyzed at the peak of disease (day 10 after challenge). Pamidronic acid strategies for neuroprotection are urgently sought and require a detailed understanding of the mechanisms underlying neuronal damage. The key contribution of cytotoxic CD8+ T lymphocytes (CTLs) to this process has become increasingly appreciated in recent years (Neumann et al., 2002). CTLs are commonly recruited to the brain in viral infections, paraneoplastic disorders (Albert and Darnell, 2004), and autoimmune diseases such as multiple sclerosis (MS) and Rasmussens encephalitis (RE; Hauser et al., 1986; Bien et al., 2005; Friese and Fugger, 2005; Goverman, 2009). Upon engagement of their cognate peptideCMHC class I (MHC-I) complex on target cells, CTLs activate an array of effector functions. Cytotoxicity is typically mediated by perforin-dependent mechanisms and FasCFasL (CD95/CD95L) Pamidronic acid interactions (Stinchcombe and Griffiths, 2007), but CTLs also secrete cytokines including Pamidronic acid IFN- and TNF. The relative contribution of each of these pathways to tissue damage varies greatly and depends on the target cell type and tissue (Guidotti et al., 1996; K?gi et al., 1996; Medana et al., 2000). At the same time, CTL cytotoxicity and cytokine secretion can also both contribute to computer virus control in the CNS (Binder and Griffin, 2001; Shrestha and Diamond, 2007; Pinschewer et al., 2010b). Neurons show limited turnover and regenerative capacity yet serve essential functions. Classical concepts have therefore suggested that neurons are spared from CTL attack. Pamidronic acid This immune privilege has been accredited to limited MHC-I expression (Joly et al., 1991), secretion of immunomodulatory TGF- (Liu et al., 2006), and expression of Fas-L (Medana et al., 2001a). The same mechanisms are also thought to symbolize an evolutionary reason why neurons serve as a sanctuary for several RNA and DNA viruses, namely members of the families (Brown et al., 1979; Sequiera et al., 1979; ter Meulen et al., 1984; Joly et al., 1991). Recent studies have shown, however, that infected neurons do not escape CTL recognition altogether (McDole et al., 2010). For example, CNS-infiltrating CTLs established stable peptide/MHC-ICspecific contacts with Herpes simplex virusC or Borna disease virusCinfected neurons, respectively (Khanna et al., 2003; Chevalier et al., 2011). In the Theilers murine encephalomyelitis computer virus model, depletion of CTLs or genetic deficiency in MHC-I or perforin preserved axon integrity and prevented neurological deficits (Murray et al., 1998; Deb et al., 2009, 2010). CTLs can attack neuronal somata (Manning et al., 1987) and axons (Medana et al., 2001b) in main neuronal cultures and explants, and cultured neurons are sensitive to lysis or silencing by perforin (Rensing-Ehl et al., 1996; Meuth et al., 2009). The Fas/Fas-L pathway can cause cytoskeleton breaks and membrane disruption which eventually cause neuronal death (Medana et al., 2000). However, the morphology, electrical activity, and glial cell environment of neurons differ considerably between in vitro culture conditions and the natural tissue habitat, and all of these factors can affect susceptibility to CTL attack (Neumann et al., 1995). Hence, we still lack a Rabbit Polyclonal to PC clear understanding of how CTLs damage neurons in vivo and which alterations result from such damage. We have recently established the viral dj vu model, allowing us to study CTL-mediated neuronal damage and the producing disease in vivo (Merkler et al., 2006). Neonatal intracranial (i.c.) contamination of mice with an attenuated lymphocytic choriomeningitis computer virus (LCMV) variant (rLCMV/INDG) results in viral persistence selectively in CNS neurons (a status referred to as carrier mice). rLCMV/INDG is not cytolytic and carrier mice are therefore clinically healthy, but they express viral nonself-antigens in neurons. Notably, they are free of CNS-infiltrating T cells, and viral epitope-specific CD8+ T cell frequencies in peripheral blood remain below detection limits of peptide/MHC-I tetramer measurements (Merkler et al., 2006). This indicates that neonatal rLCMV/INDG contamination fails to trigger a clinically significant CTL response. Upon adult contamination with LCMV WT (LCMVwt; referred to as challenge), carrier mice mount vigorous CTL responses against the immunodominant H-2DbCrestricted nucleoprotein-derived epitope NP396 that is shared between rLCMV/INDG and LCMVwt. These CTLs infiltrate the CNS gray matter, attack NP396-expressing rLCMV/INDG-infected neurons, and cause severe disease within 7C10 d after challenge. The topographical distribution and the composition of inflammatory infiltrates in viral dj vu disease.