MHC-Independent Genetic Factors Control the Magnitude of CD4+ T Cell Responses to Amyloid-β Peptide in Mice through Regulatory T Cell-Mediated Inhibition

Accumulation of amyloid-beta peptide (A beta) is considered the triggering factor of pathogenic lesions in Alzheimer's disease (AD), and vaccines targeting A beta are promising therapeutic options. However, the occurrence of meningoencephalitides attributed to T cell responses in 6% of A beta-immunized patients underscores the need for a better understanding of T cell responses to A beta. We characterized the parameters controlling the magnitude of A beta-specific CD4(+) T cell responses in mice. T cell responsiveness to A beta 1-42 was highly heterogeneous between mouse strains of different H-2 haplotypes, with SJL/J (H-2(s)) mice displaying a strong response, mainly specific for A beta 10-24, and C57BL/6 (H-2(b)) mice displaying a weak response to A beta 16-30. Surprisingly, C57BL/6 mice congenic for the H-2(s) haplotype (B6.H-2(S)), which display a permissive MHC class II allele for presentation of the immunodominant A beta 10-24 epitope, showed a very weak CD4(+) T cell response to A beta, suggesting that MHC-independent genes downmodulate A beta-specific CD4(+) T cell responses in C57BL/6 background. Vaccine-induced CD4(+) T cell responses to A beta were significantly enhanced in both C57BL/6 and B6.H-2(S) mice upon depletion of regulatory T cells (Tregs), whereas Treg-depleted SJL/J mice displayed unaltered A beta-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 A beta-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 A beta-specific Treg responses. The Journal of Immunology, 2011, 187: 4492-4500.