Abstract Details

Title Astrocytic MHC-I but Not MHC-II Regulates EAE Disease Severity

Topic Multiple Sclerosis

Presentation(s) S17 - Multiple Sclerosis: Immunology/Basic Sciences (2:36 PM-2:48 PM)

Poster/Presentation
Number 009

Objective To test whether astrocytic major histocompatibility complex-I (MHC-I) and –II (MHC-II) regulate disease severity in experimental autoimmune encephalomyelitis (EAE).

Background Reactive astrocytes upregulate the antigen presentation receptors, MHC-I and MHC-II, in lesions of viral encephalitis, multiple sclerosis and the animal model of CNS autoimmune disease, EAE. MHC-I and –II bind antigen-specific T cell receptors (TCRs) on CD8⁺ and CD4⁺ T cells, respectively, to drive T cell proliferation. Whether astrocytic antigen presentation contributes to CNS autoimmune disease pathophysiology is still unknown. The potential for antigen-specific regulation of immune cell proliferation by astrocytes, a local CNS resident cell population with CNS barrier properties, suggests a novel translational checkpoint against CNS inflammation.

Design/Methods We created transgenic astrocyte-specific conditional MHC-I and MHC-II knock-out (CKO) mouse lines by crossing the astrocyte-specific promoter line, B6.Cg-Tg(Gfap-cre)77.6Mvs/2J, with the B6(Cg)-B2m^{tm1c(EUCOMM)Hmgu}/J and B6.129X1-H2-Ab1^b-tm1Koni/J lines, respectively. CKO (homozygous floxed mice with Gfap-Cre) and littermate wild-type (WT) controls (homozygous floxed animals without Gfap-Cre) were subjected to EAE at 10-12 weeks of age and then rated blind to genotype for 35 days from disease onset. Immunohistochemistry for neuropathological measures of astrocyte activation (GFAP), neuronal cell death (NeuN), demyelination (fluoromyelin) and remyelination (Olig2) were also performed at peak disease, 5 days from disease onset, and the chronic time point, 35 days from disease onset.

Results MHC-I CKOs showed a more severe course of EAE compared to WTs and this phenotype was most pronounced in males compared to females. In contrast, MHC-II CKOs showed no significant difference in the course of EAE.

Conclusions

Loss of astrocytic MHC-I, but not MHC-II, leads to increased disease severity in EAE, suggesting that astrocytic presentation of antigen to CD8⁺T cells, but not CD4⁺ T cells, regulates the pathophysiology of EAE. Astrocyte-CD8⁺T cell crosstalk represents a potential translational checkpoint for CNS autoimmune disease.

Authors/Disclosures
Sam H. Horng, MD, PhD PRESENTER	The institution of Dr. Horng has received research support from National Institutes of Health . The institution of Dr. Horng has received research support from Jayne and Harvey Beker Foundation .
Jorge Villavicencio (Icahn School of Medicine Mount Sinai)	No disclosure on file
Mario Amatruda (Icahn School of Medicine at Mount Sinai)	No disclosure on file

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