PD-1 is an inhibitory receptor induced in T cells after activation and regulates the balance between stimulatory and inhibitory signals that plays a vital role in the induction and maintenance of anergy and peripheral tolerance. By inhibiting T effector cell function, PD-1 signaling mediates tissue tolerance by suppressing tissue-reactive T cells and protects against immune-mediated tissue damage. PD-1 can also regulate T cell tolerance by promoting the generation of Treg cells. PD-1 requires proximity and co-ligation with the TCR, resulting in tyrosine phosphorylation of the ITSM motif in C-terminus of PD-1 cytoplasmic tail leading to the recruitment of SHP-2 and inhibition of multiple downstream activation pathways. Our recent work has provided mechanistic insights of how PD-1-TCR/CD3 co-ligation affects T cell signaling pathways that mediate induction of anergy, alters metabolic reprogramming and impacts the differentiation program of T effector cells. In the present exploratory application, we will test a novel hypothesis that co-ligating PD-1 and TCR is a novel approach to suppress aberrantly activated T cells. To this end, we will generate a single chain diabody termed PD1-scDb to co-engage PD-1 and TCR/CD3 to suppress T cell activation. This conceptually and technically novel approach is in stark contrast to the mainstream current approaches, which aim to block PD-1-mediated inhibitory signaling with the goal to enhance T cell activation. To demonstrate the potential therapeutic application of our novel compound to tame aberrantly activated T cells we will test its ability to reverse the signaling, metabolic and functional aberrations of autoreactive T cells and ameliorate symptoms of systemic lupus erythematosus (SLE), the prototype autoimmune disease. For this purpose we generated a prototype hPD1-scDb that showed potent inhibition of T cell responses, providing proof-of-concept of our novel idea and feasibility of our technical innovation. In our present proposal, we will use hPD1-scDb to investigate the molecular and biochemical mechanisms of its function and its ability to suppress responses of autoreactive T cells from patients with SLE. We will also generate a mouse (m) PD1-scDb and investigate its immunosuppressive properties in vitro and in vivo using mouse models of SLE. To achieve our goals we will pursue the following specific aims: SA1. To determine the effects of mPD1-scDb ex vivo and in vivo using mouse models of SLE. SA2. To identify the effects of hPD1-scDb on T cells from patients with SLE.

Public Health Relevance

Our present exploratory studies will test the hypothesis that PD-1-TCR/CD3 simultaneous co- ligation by a bispecific antibody will inhibit aberrantly activated autoreactive T cells. If such approach is successful, it will have significant clinical implications because it will provide a new approach of treatment for T cell-dependent pathologies such as autoimmune diseases, graft versus host disease and transplant rejection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR073494-01A1
Application #
9823100
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
2019-09-04
Project End
2021-06-30
Budget Start
2019-09-04
Budget End
2020-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215