A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT
Jennifer L. Gommerman, Keith Giza, Stuart Perper, Irene Sizing, Apinya Ngam-ek, Cheryl Nickerson-Nutter, Jeffrey L. Browning
Jennifer L. Gommerman, Keith Giza, Stuart Perper, Irene Sizing, Apinya Ngam-ek, Cheryl Nickerson-Nutter, Jeffrey L. Browning
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Article Autoimmunity

A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT

Abstract

In studies using genetically deficient mice, a role for the lymphotoxin (LT) system in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has remained controversial. Here, we have reassessed this conclusion by using a fusion protein decoy that blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. We have found that inhibition of the LT pathway prevented disease in two models of EAE that do not rely on the administration of pertussis toxin. Surprisingly, disease attenuation was due to specific blockade of LTαβ binding rather than the binding of LIGHT to its receptors. In a third system that requires pertussis toxin, LT inhibition did not affect disease, as was observed when the same model was used with LT-deficient mice. Disease prevention in pertussis toxin–free models was associated with defects in T cell responses and migration. When the DO11.10 T cell transgenic system was used, inhibition of the LT pathway was shown to uncouple T cell priming from T cell recall responses. Therefore, it is hypothesized that the LT pathway and its ability to maintain lymphoid microenvironments is critical for sustaining late-phase T cell responses in multiple sclerosis.

Authors

Jennifer L. Gommerman, Keith Giza, Stuart Perper, Irene Sizing, Apinya Ngam-ek, Cheryl Nickerson-Nutter, Jeffrey L. Browning

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KJ126+ DO11.10 T cells expand normally in vivo in LTβR-Ig–treated mice, ...
KJ126+ DO11.10 T cells expand normally in vivo in LTβR-Ig–treated mice, but ex vivo recall responses are impaired. (a) DO11.10 T cell expansion in vivo at days 2, 5, and 7 after immunization is represented as percentage of CD4+ T cells that are KJ126+. DO11.10 T cells were transferred to control huIgG-treated (gray bars) or LTβR-Ig–treated (black bars) BALB/c recipients, and the mice were then immunized with OVA323–339 plus CFA (gray and black bars) or not immunized (white bars). (b) Proliferation of DO11.10 T cells was assessed in vivo by prelabeling KJ126+ CD4+ T cells with CFSE and transferring these cells to recipients that were not immunized (top panel) or immunized with OVA323–339 plus CFA and treated with huIgG (middle panel) or LTβR-Ig (bottom panel) as in a. A representative FACS plot 5 days after immunization is shown here, and in each experiment five immunized animals (both treatment groups) and three unimmunized animals were evaluated separately. (c) Proliferation of CD4+ T cells from control huIgG-treated mice (diamonds) was compared with that of LTβR-Ig–treated mice at day 7 (circles). CD4+ T cells from nonimmunized mice were used as controls (squares). These experiments were performed three times with similar results. (d) Proliferation of CD4+ KJ126+ T cells was assessed using CFSE labeling at day 7. CD4+ KJ126+ T cells from control huIgG-treated mice stimulated with OVA323–339 (gray line) were compared with that of LTβR-Ig–treated mice (black line) and unstimulated LN cells (dotted line). These data are representative of three separate mice.