Abstract
MRI is sensitive to tissue pathology in multiple sclerosis (MS); however, most lesional MRI findings have limited correlation with disability. Chronic T1 hypointense lesions or “T1 black holes” (T1BH), observed in a subset of MS patients and thought to represent axonal damage, show moderate to strong correlation with disability. The pathogenesis of T1BH remains unclear. We previously reported the first and as of yet only model of T1BH formation in the Theiler's murine encephalitis virus induced model of acute CNS neuroinflammation induced injury, where CD8 T-cells are critical mediators of axonal damage and related T1BH formation. The purpose of this study was to further analyze the role of CD8 and CD4 T-cells through adoptive transfer experiments and to determine if the relevant CD8 T-cells are classic epitope specific lymphocytes or different subsets. C57BL/6 mice were used as donors and RAG-1 deficient mice as hosts in our adoptive transfer experiments. In vivo 3-dimensional MRI images were acquired using a 7 Tesla small animal MRI system. For image analysis, we used semi-automated methods in Analyze 9.1; transfer efficiency was monitored using FACS of brain infiltrating lymphocytes. Using a peptide depletion method, we demonstrated that the majority of CD8 T-cells are classic epitope specific cytotoxic cells. CD8 T-cell transfer successfully restored the immune system's capability to mediate T1BH formation in animals that lack adaptive immune system, whereas CD4 T-cell transfer results in an attenuated phenotype with significantly less T1BH formation. These findings demonstrate contrasting roles for these cell types, with additional evidence for a direct pathogenic role of CD8 T-cells in our model of T1 black hole formation.
Highlights
Multiple sclerosis is the leading cause of disability among young adults in the western world [1]
Adoptive cell transfer experiments T1 black holes (T1BH)-s were observed in all Theiler’s Murine Encephalomyelitis Virus (TMEV) infected experimental groups (Figure 1)
The above results reinforce that CD8 T cells play the predominant role in the pathogenesis of T1BH formation, and clarifies that the leading contribution in this process is by epitope specific cytotoxic CD8 T cells
Summary
Multiple sclerosis is the leading cause of disability among young adults in the western world [1]. TMEV infection in mice is an accepted model of multiple sclerosis [7,8]. In this model, mice of susceptible genetic background develop a biphasic disease; the late or chronic phase is characterized by chronic-progressive demyelination. C57BL/6 mice, infection with Theiler’s Murine Encephalomyelitis Virus (TMEV) results in the MRI phenomenon of T1BH formation [10]. It is important to note that C57BL/6 mice represent a resistant strain, meaning that chronic-progressive demyelination doesn’t develop in this model. The observed T1 black holes appear in the context of acute neuroinflammation in the early stage of viral infection; axonal damage, the most specific and pathognomonic process that characterizes T1 black holes in MS, is observed in these areas in our model [10,11]. CD8 Tcells have been associated with axonal injury in the TMEV model [13,14,15,16,17], contribute to the development of autoimmune responses in this model [18] and play a critical role in inducing severe blood-brain barrier permeability under specific conditions [19,20,21,22]
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