Two discreet subsets of CD8 T cells modulate PLP_91-110 induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice

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• 作者：Ashutosh K. Mangalam^a ; David Luckey^a ; Shailendra Giri^b ; Michele Smart^a ; Larry R. Pease^a ; Moses Rodriguez^a ; ^c ; Chella S. David^a ; ^{david.chella@mayo.edu}
• 关键词：Experimental autoimmune encephalomyelitis ; Multiple sclerosis ; HLA class II transgenic mice ; Demyelination ; Cytokine ; CD8 regulatory T cells
• 刊名：Journal of Autoimmunity
• 出版年：2012
• 期刊代码：101_08968411
• 类别：imm
• 出版时间：June, 2012
• 卷：38
• 期：4
• 页码：344-353
• 文件大小：1247 K

摘要

Previously we showed that transgenic mice expressing human HLA-DR3 gene are susceptible to PLP_91-110 induced experimental autoimmune encephalomyelitis (EAE) and can serve as an animal model of multiple sclerosis (MS). HLA-DR3 mice with EAE showed increased number of CD8 T cells indicating their important role in disease pathogenesis. The role of CD8 T cells in MS, an inflammatory demyelinating disease of CNS, has been enigmatic as it has been assigned both regulatory and pathogenic roles. Therefore, to evaluate the role of CD8 T cells, we generated CD8 deficient HLA-DR3 transgenic mice (DR3.CD8^{鈭?鈭?/sup>). Immunization with PLP_91-110 led to more severe EAE in DR3.CD8鈭?鈭?/sup> mice compared to HLA-DR3 mice indicating a regulatory role for CD8 T cells. Interestingly, DR3.CD8鈭?鈭?/sup> mice with EAE showed decreased CNS pathology compared to DR3 mice thus suggesting a pathogenic role for CD8 T cells. We show that these two subsets of CD8 T cells can be differentiated based on the surface expression of CD122 (IL-2 R尾 chain). CD8 T cells expressing CD122 (CD8+CD122+) play a regulatory role while CD8+CD122鈭?T cells act as a pathogenic subset. CD122 expressing CD8 T cells are the regulatory subset of CD8 T cells and regulate the encephalitogenic CD4 T cells through direct modulation of antigen presenting cells and/or through the release of immunoregulatory cytokines such as IL-10, IFN纬 and TGF尾. We also showed that adoptive transfer of CD8CD122鈭?T cells caused increased spinal cord demyelination indicating that these are pathogenic subset of CD8 T cells. Our study suggests that CD8+ T cells play both regulatory as well as pathogenic role in disease pathogenesis of EAE. A better understanding of these subsets could aid in designing novel therapy for MS patients.}