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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-alpha 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.

Original publication

DOI

10.1096/fj.08-116087

Type

Journal article

Journal

FASEB J

Publication Date

06/2009

Volume

23

Pages

1672 - 1684

Keywords

Animals, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, CD4 Antigens, Cycloheximide, Cytokines, Encephalomyelitis, Autoimmune, Experimental, Humans, Interleukin-2 Receptor alpha Subunit, Lectins, C-Type, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, PrPC Proteins, Protein Synthesis Inhibitors, Sepsis, Streptococcal Infections, T-Lymphocytes