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Insights into Gene Expression of Activated Pathogenic Autoimmune T Cells - Studies in Experimental Multiple Sclerosis-like Model

Ewa Kozela, Ana Juknat, Fuying Gao, Giovanni Coppola, Nathali Kaushansky and Zvi Vogel

Multiple Sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases driven by pathogenic memory T cells. Using myelin oligodendrocyte glycoprotein (MOG) 35-55-specific encephalitogenic T cells (TMOG) isolated from MOG35-55-immunized EAE mice we describe here their gene expression profile following antigen specific activation. A vast number of pro-inflammatory genes including cytokines, chemokines and growth factors (e.g., Csf2, Il3, Ccl1, Ccl3) as well as signaling pathways (e.g., iNOS, MAPK, JAK/STAT, NFκβ) were dramatically upregulated following MOG35-55 stimulation of TMOG cells. A number of Th17-related pathways were induced confirming potent Th17-like activation of TMOG. Interestingly, genes known for their anti-inflammatory role (Sit1, Hsd11b1, Pias3, Pparg, Lgmn, Klk3, Tnfaip8l2) were down-regulated in response to MOG35-55 suggesting that silencing of intrinsic suppressory mechanisms may underlie the hyperactivation of memory T cells. MOG35-55 activation led to lower transcription of pro-apoptotic/autophagic genes (Ddit4, Bbc3, Dapk2, Wbp1) and to enhanced level of anti-apoptotic transcripts (Bcl2l1). Transcripts related to toll-like receptors and MyD88-signaling were induced, revealing the involvement of innate immunity pathways in T cell driven autoimmunity. This study reveals the transcriptional events that lead to enhanced cytotoxicity, proliferation and resistance to apoptosis of activated autoimmune T cells. We suggest that encephalitogenic T cells may serve as a reliable in vitro model for screening for possible therapeutics against T cell driven autoimmune diseases.