Dissecting Chimeric Antigen Receptor Function in Human Regulatory T Cells
Contact PI: Leonardo Ferreira, PhD, Medical University of South Carolina
Start Date: March 2021
HIRN Emerging Leader Award Recipient
Abstract
The adaptive immune system has evolved to specifically recognize and destroy a virtually infinite variety of pathogens, while remaining unresponsive towards self-tissues, a state known as immune tolerance. Regulatory T cells (Tregs) play a pivotal role in inducing and maintaining tolerance, as dramatically illustrated by the lethal multi-organ autoimmunity that arises in their absence. Manipulating human Tregs has the potential to restore tolerance to treat autoimmunity. Yet, minute numbers of antigen-specific Tregs and Treg instability upon prolonged expansion have hampered the implementation of Treg-based adoptive cell therapies. Moreover, the antigens recognized by Tregs remain largely unknown, impeding progress in the field. Chimeric antigen receptor (CAR) technology has greatly expedited the generation of antigen-specific T cells. CARs are synthetic receptors comprising an extracellular antigen-binding domain and an intracellular signaling domain, enabling T cell activation by an antigen of choice. CAR T cell therapies, FDA-approved to treat B cell malignancies, have led to remission rates higher than with any previously approved drug, transforming cancer treatment. A CAR can be designed to redirect a Treg to a specific target antigen. Generating CAR Tregs specific for islet antigens is the most efficient way to target them to the affected area in T1D. However, cytotoxicity has been found to be one of the multiple mechanisms utilized by Tregs to suppress immune responses. For instance, both granzyme B and perforin have been found to be required for optimal Treg suppression of tumor clearance by either eliminating antigen presenting cells or CD8+ T cells and NK cells directly. In our hands, CAR Tregs can be cytotoxic towards target antigen-expressing cells. Thus, targeting CAR Tregs to pancreatic islet cells poses the risk to damage the very cells to be protected from immune attack. Determining the extent and universality of the inflammatory and cytotoxic properties of CAR Tregs is of utmost importance to comprehend CAR Treg function and ensure the safe translation of CAR Tregs to treat T1D patients.
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