Project 1 - Modulation of Tolerance and Autoimmunity by Inhibitory Receptors

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY Inhibitory receptors (IRs) PD1 and LAG3 play critical roles in regulating T cell tolerance and preventing autoimmunity, but limit effective immunity against tumors and chronic infections. These IRs are major clinical targets. PD1 blockade has transformed cancer therapy, and PD1 agonists are in clinical trials for autoimmunity. Combined LAG3/PD1 blockade recently received FDA approval for melanoma. However, IR blockade may lead to immune-related adverse events (irAEs). A better understanding of how PD1/LAG3 interact to control tolerance is needed to determine how to effectively modulate these IRs to activate anti-viral and anti-tumor T cells while minimizing irAEs, and develop optimal PD1/LAG3 agonists for autoimmunity. Project 1 (P1) will test the hypothesis that “PD1 and LAG3 enforce tolerance through a combination of overlapping and unique cell-intrinsic and cell-extrinsic functions in CD4+ and CD8+ T cells to control the balance between pathogenic and protective T cell responses during autoimmunity”. P1 will use two autoimmune disease models—experimental autoimmune encephalomyelitis (EAE) and compare self-reactive T cells in the non-obese diabetes (NOD) model—to identify shared mechanisms and two target organs. Aim 1: What are the relative and synergistic roles of PD1 and LAG3 in controlling self-reactive CD4+ FoxP3- (Tconv) and regulatory T (Treg) cells during EAE initiation and progression? We hypothesize the relative and integrated functions of PD1 and LAG3 differ during EAE initiation and progression. We will determine (A) cell-intrinsic functions of PD1 and LAG3 in regulating self-reactive naïve and effector Tconv; (B) integrated effects of LAG3/PD1 modulation on Treg and Tconv during the course of EAE; and (C) shared and unique molecular pathways downstream of PD1/LAG3 in CD4+ T cells in EAE. We will use a combination of CD4+ T cell restricted and inducible PD1/LAG3-deficient model systems and PD1/LAG3 recombinant antibodies. Aim 2: What are the molecules and mechanisms downstream of PD1 and LAG3 that control self-reactive CD8+ T cells during autoimmune diabetes? We hypothesize there are shared drivers of exhausted/effector-like CD8+ T cells in autoimmunity, cancer and chronic infection. We will determine: (A) how PD1/LAG3 interact to control diabetogenic CD8+ T cells; (B) how PD1/LAG3 interact to regulate the balance between pathogenic and protective T cells during diabetes; and (C) causal genes driven by PD1/LAG3 to regulate activation, differentiation, and effector functions of diabetogenic T cells. We will use a combination of CD8+ T cell restricted PD1/LAG3-deficient model systems and PD1/LAG3 recombinant antibodies. In both Aims, we will use cellular and transcriptomic approaches to assess changes associated with LAG3/PD1 loss in T cells, and gene perturbation approaches to define mechanisms by which PD1/LAG3 control T cell fate and function. IR-PPG Interactions: P1 will collaborate with P2 and P3 to define shared and unique mechanisms of LAG3/PD1 function in T cells in autoimmunity, cancer (P2) and chronic viral infection (P3); Core A to exchange data; Core B to obtain mice; Core C for computational analyses and gene perturbation, and Core D to obtain antibodies.