UCLA researchers in the Department of Pediatrics have developed a suite of novel spherical aAPCs of varying sizes and densities, that can be coupled with an oscillatory stimulus to promote efficient T cell activation: offering the possibility to aptly engineer T cells for a variety of clinical and experimental needs.
BACKGROUND:
T cells circulate throughout the body and coordinate immune response to pathogens recognized by their foreign proteome. Activation of T cells begins through the engagement of T cell receptors (TCRs) with the major histocompatibility complex (MHC) of antigen-presenting cells (APCs). It is additionally recognized that activation of the TCR by MHC engagement requires a mechanical force. Ex vivo cultivation of T cells is vital for manufacturing several different cellular therapies (e.g., chimeric antigen receptor (CAR) therapies), so much attention has been devoted to optimizing polyclonal T cell cultivation. While many advances have been made with polymer beads coated with stimulatory factors, known as artificial antigen-presenting cells (aAPCs), ex vivo cultivation of T cells is still unfavorable. Additional studies have shown that the mechanical force necessary to activate TCRs, can be substituted by exogenous sources. However, this process entailed contact with single T cells and thus would not be compatible with large numbers of T cells. Therefore, a current need exists to utilize advances in aAPCs, while also facilitating the need for exogenous forces that will trigger efficient ex vivo T cell activation for several clinical and experimental needs.
INNOVATION:
UCLA researchers have developed a suite of novel spherical aAPCs of varying sizes and densities that can be coupled with an oscillatory stimulus to promote efficient T cell activation. The developed aAPCs were constructed to offer various degrees of curvature for enhanced TCR engagement with coated stimulatory factors. The oscillatory stimulus was delivered to the T cell culture spiked with aAPCs, to determine the ability to stimulate the TCR, for increased T cell activation. External stimuli, coupled with the developed aAPCs dramatically improved activation beyond the conventional Dynabead-based approach to T cell activation: promoting the cellular proliferation of T cells by a factor of two. The researchers further tested the ability to activate induced regulatory T cells (iTreg), that are particularly sensitive to high levels of stimulation. Under optimized conditions, the aAPCs showed an almost three-fold higher induction of iTreg cells compared to Dynabeads. The researchers further showed the ability to endow the aAPCs with the ability to secrete cytokines to promote iTreg development. These examples show that external mechanical stimulus coupled with tunable aAPCs (e.g., size/curvature, signal density, and cytokine secretion) offer the ability to engineer T cells in a highly efficient manner for a variety of clinical and experimental needs.
POTENTIAL APPLICATIONS:
• Activation of T cells ex vivo
• Inductions of induced regulatory T cells ex vivo
ADVANTAGES:
• Higher activation and proliferation rates of T cells compared to conventional methods
• Greater induction of induced regulatory T cells
• Ability to secrete cytokines to further promoter induced regulatory T cell production
• Range of sizes and densities of artificial antigen-presenting cells
DEVELOPMENT-TO-DATE:
Three libraries of artificial antigen-presenting cells have been developed and tested. These particles were tested with T cells for activation efficacy as measured by FACS analysis of CD4 and CD8. Similarly, the formation of induced regulatory T cells (iTreg cells) was analyzed by flow cytometry for Foxp3 and CD25 co-expression.