Accumulation of amyloid-β peptide (Aβ) is considered the triggering factor of pathogenic lesions in Alzheimer’s disease (AD), and vaccines targeting Aβ are promising therapeutic options. However, the occurrence of meningoencephalitides attributed to T cell responses in 6% of Aβ-immunized patients underscores the need for a better understanding of T cell responses to Aβ. We characterized the parameters controlling the magnitude of Aβ-specific CD4+ T cell responses in mice. T cell responsiveness to Aβ1-42 was highly heterogeneous between mouse strains of different H-2 haplotypes, with SJL/J (H-2s) mice displaying a strong response, mainly specific for Aβ10-24, and C57BL/6 (H-2b) mice displaying a weak response to Aβ16-30. Surprisingly, C57BL/6 mice congenic for the H-2s haplotype (B6.H-2S), which display a “permissive” MHC class II allele for presentation of the immunodominant Aβ10-24 epitope, showed a very weak CD4+ T cell response to Aβ, suggesting that MHC-independent genes downmodulate Aβ-specific CD4+ T cell responses in C57BL/6 background. Vaccine-induced CD4+ T cell responses to Aβ were significantly enhanced in both C57BL/6 and B6.H-2S mice upon depletion of regulatory T cells (Tregs), whereas Treg-depleted SJL/J mice displayed unaltered Aβ-specific T cell responses. Finally, Treg depletion in C57BL/6 transgenic APPPS1 mice, a mouse model of AD, results in enhanced vaccine-induced CD4+ T cell responses in AD compared with wild-type animals. We concluded that the magnitude of Aβ-specific CD4+ T cell responses is critically controlled in both physiological and pathological settings by MHC-independent genetic factors that determine the overall potency of Aβ-specific Treg responses.

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Class I MHC-restricted T cell responses have been shown to be critical for the development of immune resistance to Trypanosoma cruzi in mice. However, to date, no antigenic targets of this anti-parasite response have been characterized. We have analyzed the characteristics of potential T. cruzi CTL target molecules by expression of the model CTL target molecule chicken OVA in different cellular compartments of T. cruzi. OVA (amino acids 139-385) was expressed as a secretory, cytoplasmic, transmembrane, or glycosylphosphatidylinositol-anchored protein in T. cruzi transfectants. Host cells infected with T. cruzi transfectants that secreted or released OVA, but not those producing cytoplasmic or transmembrane forms of OVA, could process and present OVA peptide via the class I MHC pathway, as indicated by the stimulation of OVA-specific CD8+ T cell hybridomas and the cytolysis of host cells infected with OVA-secreting parasites by OVA-specific CTLs. In addition, infection of mice with OVA-secreting parasites elicited the production of OVA-specific CTLs. These studies demonstrate the ability to target proteins to specific cellular compartments in T. cruzi using either trypanosomal or mammalian signal sequences. Furthermore, these results suggest that proteins secreted or released by T. cruzi in infected cells are a major source of peptides for MHC class I presentation and for the generation of parasite-specific CTL.