Inflammation (arrows) is focused on the cerebellum, not the spine, in mice lacking the IFN receptor.

IFN, the signature T helper (Th)-1 cytokine, contributes to CNS inflammation during EAE. But not all forms of EAE are alike. In classical EAE, the T cell attack is focused on the spinal cord. But in atypical disease, the cerebellum and brain stem are the primary victims. A prior study suggested that the ratio of interleukin (IL)-17 to IFN determines whether disease pathology occurs in the spine or brain, with increasing levels of IL-17 associated with disease in the brain. But the data from Lees et al. instead show that lesion location is mainly controlled by the brain's response to IFN.

When transferred into wild-type mice, the authors show, myelin-specific Th1 cells attacked the spinal cord. But when transferred into mice lacking the IFN receptor, the cells instead attacked the cerebellum and brain stem, sparing the spinal cord. The production of IL-17 by the transferred T cells was comparable in both settings. However, the production of IL-17 by non-T cells predominated in the cerebellum, suggesting that IL-17–producing cells contribute to atypical disease but do not determine its location.

In agreement with past reports, however, transferring mixed populations of IFN- and IL-17–producing cells resulted in a mixed disease phenotype, with increasing numbers of IFN producers causing progressively more spinal cord disease.

Why IFN induces inflammation in one tissue and not another remains unknown—particularly because no obvious regional differences in the expression of the receptor were detected. The authors suspect that IFN triggers a localized production of T cell–attracting chemokines in the spine.