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Several hurdles must be overcome in order to achieve efficient and safe immunotherapy against conformational neurodegenerative diseases. In prion diseases, the main difficulty is that the prion protein is tolerated as a self protein, which prevents powerful immune responses. Passive antibody therapy is effective only during early, asymptomatic disease, well before diagnosis is made. If efficient immunotherapy of prion diseases is to be achieved, it is crucial to understand precisely how immune tolerance against the prion protein can be overcome and which effector pathways may delay disease progression. To this end, we generated a transgenic mouse that expresses the ß-chain of a T cell receptor recognizing a PrP epitope presented by the class II major histocompatibility complex. The fact that the constraint is applied to only one TCR chain allows adaptation of the other chain according to the presence or absence of tolerogenic PrP. We first show that transgene-bearing T cells, pairing with rearranged α-chains conferring anti-PrP specificity, are systematically eliminated during ontogeny in PrP+ mice, suggesting that precursors with good functional avidity are rare in a normal individual. Second, we show that transgene-bearing T cells with anti-PrP specificity are not suppressed when transferred into PrP+ recipients and proliferate more extensively in a prion-infected host. Finally, such T cells provide protection through a cell-mediated pathway involving IL-4 production. These findings support the idea that cell-mediated immunity in neurodegenerative conditions may not be necessarily detrimental and may even contribute, when properly controlled, to the resolution of pathological processes., Author Summary It is generally accepted that prion-specific antibodies can protect against mouse scrapie infection. However, passive antibody therapy is limited to the lymphoinvasion stage of the disease. Active immunization has been attempted but the results have been disappointing. There is therefore a need for developing analytical models that will allow a fine dissection of the immune mechanisms at play in prion diseases and help distinguish between protective effects mediated by B cells and antibodies, and the effect of T cells. The aim of our study was to thoroughly examine T cell tolerance to the prion protein and to evaluate whether a pure specific population of T cells adoptively transferred to a normal host could proliferate and confer protection against scrapie. We designed a transgenic mouse in which the majority of T lymphocytes recognize the prion protein. Our key findings are that prion-specific T cells remain functional when transferred to normal recipients, even more so when the host is infected with scrapie, and confer partial protection against the disease by slowing down prion replication, in complete absence of anti-prion antibodies. Anti-prion T cells may therefore be considered as a therapeutic tool in the future.