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

Abstract

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.

CD4 T cells in immunity and immunotherapy of Alzheimer's disease

“…antibody isotype and titres, and the profile of T‐cell cytokines). In mice, Aβ immunogenicity markedly differs between strains; for example, Aβ is highly immunogenic in NOD and SJL mice, which have a dominant T‐cell epitope between residues 10 and 24 of Aβ, whereas the peptide evokes only weak T‐cell responses in C57BL/6 mice in which the epitope is between residues 16 and 30 . NOD congenic mice bearing the I‐A b class II allele also fail to elicit a strong T‐cell response, suggesting that the low immunogenicity of Aβ 16–30 in C57BL/6 mice is primarily a result of a low‐affinity epitope selected by the I‐A b MHC class II.…”

“…NOD congenic mice bearing the I‐A b class II allele also fail to elicit a strong T‐cell response, suggesting that the low immunogenicity of Aβ 16–30 in C57BL/6 mice is primarily a result of a low‐affinity epitope selected by the I‐A b MHC class II. However, both C57BL/6 and B6.H‐2 s congenic mice, but not SJL mice, exhibit enhanced Aβ‐specific T‐cell responses upon the depletion of regulatory T (Treg) cells, suggesting that under certain genetic backgrounds, Treg cells can significantly affect Aβ immunogenicity . As no differences in thymic expression of APP are observed between C57BL/6 and SJL mice, the mechanism behind the effect of Treg cells on Aβ immunogenicity in C57BL/6 mice and the reason it is not effective in the more Aβ‐immunogenic SJL mice are yet to be revealed.…”

A Perspective on Roles Played by Innate and Adaptive Immunity in the Pathobiology of Neurodegenerative Disorders

“…Systemic immunity affects disease pathogenesis by altering the phenotype of microglia (Heneka et al, 2015; Latta et al, 2015; Lucke-Wold et al, 2015; Mhatre et al, 2015; Yamada, 2015; Zhang and Jiang, 2015). As both Teff and Treg were theorized to play a crucial role in maintaining systemic immune homeostasis, the preservation of these cells’ immune functions is likely to control disease tempo (Saresella et al, 2010; Toly-Ndour et al, 2011; Yang et al, 2013; Schwartz and Baruch, 2014; Baruch et al, 2015; Wang et al, 2015). In support of this idea, transplantation of splenocytes acquired from young mice without CNS disease not only prevented AD, but also improved spatial learning and memory in APPswe/PSENldE9 transgenic animals (Wang et al, 2015).…”

Amyloids in Site-Specific Autoimmune Reactions and Inflammatory Responses

“…Previous review has revealed that Tregs nonspecifically inhibit CD4+ T cell proliferation both in vitro and in EAE (163). It is worth noting, according to the Dorothee group, that Tregs critically control the magnitude of CD4+ T cell targeting to amyloid-β in response to amyloid-β vaccination in both physiological and pathological settings (164). Consistently, transient depletion of Tregs in mouse models of AD accelerates the onset of cognitive deficits; conversely, amplification of Tregs improves cognitive functions (165).…”