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A role of cellular prion protein in programming T-cell cytokine responses in disease

Rebecca J. Ingram^*,1, Jeremy D. Isaacs^*,,1, Gurman Kaur^*,2, Daniel E. Lowther^*, Catherine J. Reynolds, Rosemary J. Boyton, John Collinge, Graham S. Jackson and Daniel M. Altmann^*,3

^* Human Disease Immunogenetics Group, Department of Infectious Diseases and Immunity, Hammersmith Hospital, Imperial College London, London, UK;

MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London, UK; and

Lung Immunology Group, Immunology and Infection/NHLI, Sir Alexander Fleming Building, South Kensington Campus, Imperial College London, London, UK

³Correspondence: Dept. of Infectious Diseases and Immunity, Imperial College London, Hammersmith Hospital, Du Cane Rd., London W12 0NN, UK. E-mail: d.altmann{at}imperial.ac.uk

The cellular prion protein (PrP^C) is widely expressed in neural and non-neural tissues, but its function is unknown. Elucidation of the part played by PrP^C in adaptive immunity has been a particular conundrum: increased expression of cell surface PrP^C has been documented during T-cell activation, yet the functional significance of this activation remains unclear, with conflicting data on the effects of Prnp gene knockout on various parameters of T-cell immunity. We show here that Prnp mRNA is highly inducible within 8–24 h of T-cell activation, with surface protein levels rising from 24 h. When measured in parallel with CD69 and CD25, PrP^C is a late activation antigen. Consistent with its up-regulation being a late activation event, PrP deletion did not alter T-cell-antigen presenting cell conjugate formation. Most important, activated PrP^0/0 T cells demonstrated much reduced induction of several T helper (Th) 1, Th2, and Th17 cytokines, whereas others, such as TNF- and IL-9, were unaffected. These changes were investigated in the context of an autoimmune model and a bacterial challenge model. In experimental autoimmune encephalomyelitis, PrP-knockout mice showed enhanced disease in the face of reduced IL-17 responses. In a streptococcal sepsis model, this constrained cytokine program was associated with poorer local control of infection, although with reduced bacteremia. The findings indicate that PrP^C is a potentially important molecule influencing T-cell activation and effector function—Ingram, R. J., Isaacs, J. D., Kaur, G., Lowther, D. E., Reynolds, C. J., Boyton, R. J., Collinge, J., Jackson, G. S., Altmann, D. M. A role of cellular prion protein in programming T-cell cytokine responses in disease.

Key Words: T lymphocyte • knockout mouse • Th17

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