Using Genetically Engineered Models to Study Pre-Autoimmune States

Using the RIP-NINJA mouse model to study how PD-1 regulation in the pancreas prevents autoimmune induction and checkpoint therapy-induced diabetes.
Completed Endocrine Diseases Type 1 Diabetes Animal Models Autoantigens Biological & Mechanistic Cytokine Signaling Early Disease Detection Experimental Platforms & Models Functional Genomics & CRISPR Immune Tolerance T Cell Biology Translational & Clinical

Funding Year: 2023

Project Overview

Most autoimmune research focuses on disease after symptoms appear, not on how immune tolerance first fails. PD-1 is a critical regulator that keeps harmful immune cells in check — and its blockade in cancer patients can unexpectedly trigger type 1 diabetes, even in old age. This project uses a novel mouse model, RIP-NINJA, to control when and where the immune system encounters specific self-antigens in the pancreas, enabling study of the earliest steps in autoimmune induction. Early findings show that antigen-specific T cells begin attacking insulin-producing beta cells but are restrained by PD-1, that T cell infiltration directly induces PD-L1 upregulation in beta cells, and that aPD-1 or aCTLA-4 treatment increases T cell proliferation and cytotoxicity — with Treg infiltration preceding DC infiltration.

Impact & Innovation

Catching autoimmunity before it starts.

 

The RIP-NINJA model enables precise, controlled study of the pre-autoimmune state in the pancreas — revealing how PD-1 restrains early T cell attack and what happens when that restraint is lost, with direct relevance to T1D prevention and checkpoint therapy safety.

  • Reveals that PD-1 actively restrains antigen-specific T cell cytotoxicity in the pre-autoimmune pancreas, with T cell infiltration directly inducing PD-L1 upregulation in beta cells through a unique chromatin-accessible region
  • Establishes RIP-NINJA as a versatile platform for testing genetic, dietary, and microbiome factors that promote or prevent autoimmune induction under controlled, non-autoimmune-prone conditions
  • Advances the Consortium’s Shared Mechanisms Across Autoimmune Diseases pillar by illuminating how PD-1-mediated immune regulation in the pancreas intersects with checkpoint therapy-induced diabetes and broader autoimmune susceptibility
Research Approach

A framework designed for discovery

This project uses the RIP-NINJA genetically engineered mouse model to study the earliest stages of autoimmune induction in the pancreas, focusing on how PD-1-mediated immune regulation prevents progression to overt disease and how its disruption — by checkpoint therapy or genetic deletion — triggers beta cell attack.

RIP-NINJA mouse model enabling controlled, inducible antigen expression in pancreatic beta cells; in vivo T cell infiltration and cytotoxicity studies; in vitro IFN-γ stimulation of beta cell lines to characterize PD-L1 upregulation and chromatin accessibility; aPD-1 and aCTLA-4 checkpoint blockade studies; and analysis of Treg and DC infiltration dynamics in the pre-autoimmune pancreas.

RIP-NINJA mouse model datasets tracking antigen-specific T cell behavior, PD-L1 expression, and immune cell infiltration in pancreatic islets; in vitro beta cell line data characterizing IFN-γ-induced PD-L1 upregulation via chromatin-accessible regulatory regions; and checkpoint blockade treatment datasets measuring T cell proliferation, cytotoxicity, and Treg dynamics.

Elucidation of the PD-1-dependent mechanisms that restrain autoimmune induction in the pancreas, with translational relevance to T1D prevention and the management of checkpoint therapy-induced diabetes. The RIP-NINJA platform will support future studies testing genetic, dietary, and microbiome factors that modulate autoimmune susceptibility.

Investigators & Institutions

Powering the science

Principal Investigator

Nikhil S. Joshi, PhD, Colton Consortium Member

Associate Professor, Department of Immunobiology, Yale School of Medicine, Yale University

Colton Centers & Institutions

Colton Center for Autoimmunity at Yale University

Research Outputs

From insight to impact

Publications

Organ injury in systemic autoimmunity is mediated by stem-like CD8+ T cells arising from tissue-draining lymph nodes

Immunity
Al Souz, J; Wei, Y; Cui, C; Qu, R; Choi, JY; Wang, F; Moioffer, SJ; Barrett, J; Chernova, I; Nadella, M; Siniscalco, ER; Moeckel, G; Joshi, NS; Chen, PM; Arazi, A; Ho, YC; Craft, J April 2026
Adaptive ImmunityAnimal ModelsAutoantigensBiological & MechanisticCytokine SignalingDisease SubtypingExperimental Platforms & ModelsImmune ProfilingSingle Cell TechnologiesT Cell BiologyTherapeutic DevelopmentTranslational & ClinicalSystemic DiseasesSystemic Lupus Erythematosus (SLE)Yale University

Additional Outputs

NCI R01CA237037: $557,766 (Nikhil Joshi, 5y). Chan Zuckerberg Investigator Award: $652,173.90 (Nikhil Joshi, 3y).