MHC‐Ig induces memory T cell formationin vivoand inhibits tumour growth

Abstract

Induction of a T cell mediated immune response is critical for the eradication of viral infections and tumours. Soluble peptide-loaded major histocompatibility complex-Ig (pep−MHC-Ig) have been shown to bind their cognate ligands, T cell receptor, with high affinity, and are successfully used to visualize antigen-specific T cells. Furthermore, immobilized pep−MHC-Ig can activate and expand antigen-specific T cells in vitro and in vivo. In this study, we investigate the use of pep−MHC-Ig as a potential strategy to modulate antigen specific T cell immune responses in vivo. SIY−Kb-Ig immunization, together with the pre-activation by an anti-CD40 monoclonal antibody, is able to stimulate a strong expansion of adoptively transferred 2C transgenic T cells and the formation of long term antigen-specific memory T cells. In addition, mechanistic studies show that the pep−MHC-Ig molecules directly activate T cells in vivo without requiring uptake and reprocessing by antigen-presenting cells. Furthermore, B6 mice immunized with pep−MHC-Ig molecules inhibit tumour growth in a B16-SIY melanoma prevention model. Thus, soluble pep−MHC-Ig molecules represent a powerful tool for active immunotherapy.

Commensal bacteria stimulate antitumor responses via T cell cross-reactivity

“…If SVY is indeed a cross-reactive antigen, one should be able to immunize mice and test for cross-reactive responses in vivo. Immunization of Bifidobacterium-negative Taconic mice with SVY-loaded K b complexes, as previously described (14), led to approximately 60% killing of SVY target cells in vivo and a cross-reactive killing of approximately 50% of SIY-pulsed targets in vivo ( Figure 4E). This was associated with an increased number of K b SVY effector T cells, from 0.4% to 0.6% ( Figure 4F and Supplemental Figure 9C).…”

“…Immunization assay. Recipient mice were injected intraperitoneally with 10 μg/mouse of anti-CD40 mAb (clone 3/23; BioLegend) and a day later immunized subcutaneously with 250 μg as indicated of either OVA− K b -Ig or SVY− K b -Ig dimer (14).…”

Soluble MHC class I complexes for targeted immunotherapy

“…Furthermore, it could be demonstrated that anti-CD40 mAb induced maturation of APC prior to pMC immunization was crucial for an effective immune response. Administration of anti-CD40 mAb together with or after pMC administration did not result in formation of a robust immune response, which further supports that the pMC is presented on the cell surface and not internalized [23].…”

“…It has been demonstrated that antibody Fc functionalized pMC’s can bind via Fcγ-RI and Fcγ-RIII onto professional antigenpresenting cells which enables them to activate antigen-specific T cell responses. This can be further enhanced through maturation of the APC with immune-stimulatory agents, such as lipo-poly-saccharide (LPS) [24], Poly (I:C) [32], and anti-CD40 mAb [23,33,34]. These agents cause up-regulation of Fcγ-R and expression of costimulatory molecules.…”

“…While 2C cells recognize QL9-peptide in the context of an L d -MHC molecule in an allo-response, the QL9-peptide cannot be presented on the host K b -MHC molecules. Therefore, the 2C response must be induced by one of the other two mechanisms [23]. Furthermore, it could be demonstrated that anti-CD40 mAb induced maturation of APC prior to pMC immunization was crucial for an effective immune response.…”