Comparative analysis of antigen presentation by APC subsets using a mouse model expressing multiple disease-relevant antigens — ASN Events
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  3. Comparative analysis of antigen presentation by APC subsets using a mouse model expressing multiple disease-relevant antigens

Comparative analysis of antigen presentation by APC subsets using a mouse model expressing multiple disease-relevant antigens (#121)

Camillo Bechi Genzano 1 , Kim M Becker 1 , Lucy Ho 2 , Jonathan Kon 1 , Leonor M Teles 2 , Alice A Tomei 2 , Remi J Creusot 1
  1. Department of Medicine, Columbia Center for Translational Immunology, Columbia University Medical Center, NY, United States
  2. Department of Biomedical Engineering, Diabetes Research Institute, Miami, FL, USA

Re-establishing antigen-specific tolerance is a major goal in autoimmune disease therapy. Antigen-specific strategies represent an advancement over conventional immunotherapies by selectively targeting autoreactive lymphocytes through controlled exposure to autoantigens, while preserving immune competence. These approaches employ diverse delivery modalities and target various antigen-presenting cells (APCs) to induce tolerance. However, optimal tolerogenic conditions remain undefined, underscoring the need for new mouse models to study individual APC subsets.

We generated a novel strain, termed “Inducible Diabetogenic Endogenous AntigenS” (IDEAS), carrying a Cre-inducible transgene encoding multiple Type 1 diabetes-relevant β cell epitopes and GFP on the non-obese diabetic (NOD) background. Adoptive transfer of islet antigen-reactive (IAR) T cell clones into IDEAS mice revealed low-level transgene leakiness in the absence of Cre, with recognition of multiple epitopes in lymphoid tissues, despite absent GFP expression. Transfer of IAR T cell clones into mice with full transgene expression (ubiquitous Cre, resulting in high antigen levels), stimulated a broader range of T cell clones, with pronounced activation profiles.

Different APC subtypes were evaluated ex vivo for antigen presentation using low and high endogenous antigen expression and responder BDC2.5 CD4+ T cells. CD11b+ CD11c+ dendritic cells (DCs) were the only APC capable of eliciting responses in the case of leaky antigen levels, indicating superior antigen-presenting capabilities compared to CD11b- CD11c+ CD8α+ DCs, CD11b+ CD11c- myeloid cells, and B cells. Under high antigen levels, B cells induced higher PD-1 expression on T cells compared to DCs and CD11b+ CD11c- myeloid cells.

The IDEAS mouse model enables selective evaluation of APC subset capabilities ex vivo or via adoptive transfer into syngeneic NOD mice, using APC subtypes expressing either low or high levels of antigens. A second non-leaky version of the IDEAS mouse is under development and will allow the use of different DC-specific Cre-drivers for tolerance induction in NOD mice.