title: A role of cellular prion protein in programming T-cell cytokine responses in disease.
abstract: 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.
authors.affiliation: Dept. of Infectious Diseases and Immunity, Imperial College London, Hammersmith Hospital, Du Cane Rd., London W12 0NN, UK.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ingram
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Gurman
authors.initials: G
authors.lastname: Kaur
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Lowther
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Reynolds
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Boyton
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.forename: Graham S
authors.initials: GS
authors.lastname: Jackson
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Altmann
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D003513:Cycloheximide / Q000378:metabolism; D016207:Cytokines / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018621:PrPC Proteins / Q000235:genetics / Q000276:immunology*; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D018805:Sepsis / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D003513:Cycloheximide; D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D018621:PrPC Proteins; D011500:Protein Synthesis Inhibitors; D000099192:CD69 Antigens