CD8 + T cells, which are strongly induced by most viral infections, are conceptually attractive as effector cells in autoimmunity, because most cell types express MHC class I and are, therefore, open to CD8 + T cell surveillance. Many studies of autoimmune disease have focused on CD4 + T cells, but emerging data indicate that CD8 + T cells may play a critical role. In this component of the program grant, I focus on CD8 + T cells and, in particular, on their ability to undergo bystander activation during viral infections. We postulate two general types of virus-induced bystander activation, both of which will be investigated herein. First, we have evidence that, during virus infection, a substantial proportion of naive CD8 + T cells can undergo some degree of TcR-independent bystander activation.
In Specific Aim 1, we shall: (i) evaluate howeffectively naive, primary, and memory CD8 + T cells are activated in vivo in a TcR-independent manner; (ii) determine whether naive cells, activated by these bystander effects, mature into 'bystander memory' cells; (iii) evaluate the roles of several cytokines in TcR-independent bystander activation. Second I propose a novel mechanism to explain TcR-dependent bystander activation. I suggest that virus-induced IFNgamma, up-regulates expression of the immunoproteasome and that this, in turn, leads to the presentation of new self epitopes, against which autoreactive CD8 + T cell responses may be mounted. Little is known about how, where & when the immunoproteasome is induced during virus infection, and this is the focus of Specific Aim 2.
In Specific Aim 3, we shall evaluate the role of the immunoproteasome in type 1 diabetes. These studies will be carried out together with Dr. von Herrath (PI of this program grant, and ofProject I). We shall determine immunoproteasome expression during the development of T1D, and assess whether T1D develops in the absence of the immunoproteasome. Finally, in Specific Aim 4, in collaboration with Dr. Fujinami (Project II), we shall study the role of the immunoproteasome in CNS autoimmune disease, including a new animal model of multiple sclerosis, in which CD8 + T cells appear to be the culprits.
| Schneider, Darius A; von Herrath, Matthias G (2013) Viruses and Type 1 diabetes: a dynamic labile equilibrium. Diabetes Manag (Lond) 3:217-223 |
| Van Belle, Tom L; Nierkens, Stefan; Arens, Ramon et al. (2012) Interleukin-21 receptor-mediated signals control autoreactive T cell infiltration in pancreatic islets. Immunity 36:1060-72 |
| Libbey, Jane E; Tsunoda, Ikuo; Fujinami, Robert S (2012) Possible role of interleukin-17 in a prime/challenge model of multiple sclerosis. J Neurovirol 18:471-8 |
| Boettler, Tobias; Cunha-Neto, Edecio; Kalil, Jorge et al. (2012) Can an immune-regulatory vaccine prevent HIV infection? Expert Rev Anti Infect Ther 10:299-305 |
| van Belle, Tom L; Coppieters, Ken T; von Herrath, Matthias G (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79-118 |
| Bresson, Damien; Fousteri, Georgia; Manenkova, Yulia et al. (2011) Antigen-specific prevention of type 1 diabetes in NOD mice is ameliorated by OX40 agonist treatment. J Autoimmun 37:342-51 |
| Van Belle, Tom L; Esplugues, Enric; Liao, Jeanette et al. (2011) Development of autoimmune diabetes in the absence of detectable IL-17A in a CD8-driven virally induced model. J Immunol 187:2915-22 |
| Boettler, Tobias; von Herrath, Matthias (2011) Protection against or triggering of Type 1 diabetes? Different roles for viral infections. Expert Rev Clin Immunol 7:45-53 |
| Filippi, Christophe M; Ehrhardt, Katrin; Estes, Elizabeth A et al. (2011) TLR2 signaling improves immunoregulation to prevent type 1 diabetes. Eur J Immunol 41:1399-409 |
| Libbey, Jane E; Fujinami, Robert S (2011) Experimental autoimmune encephalomyelitis as a testing paradigm for adjuvants and vaccines. Vaccine 29:3356-62 |
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