ImmunoEngineering Seminar Series
"Antigen-specific TCR–pMHC Catch Bonds Trigger Signaling by Rapid Cumulation of Force-prolonged Bond Lifetimes"
Advisor - Cheng Zhu, PhD
TCR–pMHC interactions initiate adaptive immune responses, but the mechanism of how such interactions under force induce T-cell signaling is unclear. We show that force prolongs lifetimes of single TCR–pMHC bonds for agonists (catch bonds) but shortens those for antagonists (slip bonds). Both magnitude and duration of force are important as the highest Ca2+ responses were induced by 10 pN via both pMHC catch bonds whose lifetime peaks at this force and anti-TCR slip bonds whose maximum lifetime occurs at 0 pN. High Ca2+ levels require early and rapid accumulation of bond lifetimes whereas short-lived bonds that slow early accumulation of lifetimes correspond to low Ca2+ responses. Our data support a model where force on the TCR induces signaling events depending on its magnitude, duration, frequency, and timing, such that agonists form catch bonds that trigger the T cell digitally, whereas antagonists form slip bonds that fail to activate.
"Controlled Presentation of Cytokines within 3D Mesenchymal Stem Cell Constructs to Enhance Immunomodulatory Activity"
Advisor - Todd McDevitt, PhD
Mesenchymal stem cells (MSCs) offer a potent cell therapy for the treatment of inflammatory and immune disorders due to their ability to modulate components of innate and adaptive immunity. Although MSCs have been investigated as cell therapies for diseases including graft-versus-host, type I diabetes, and inflammatory bowel diseases, clinical results thus far have been inconsistent. Recent studies have suggested that MSC immunomodulation can be greatly influenced by the cellular microenvironment and the concentration of inflammatory cytokines, including IFNγ and TNFα, which stimulate MSC immunomodulation. The low levels of cytokines observed in chronic inflammation may not be sufficient to induce MSC immunomodulation, limiting the ability of MSCs to regulate inflammation in these disease states. Engineering the local microenvironment within MSC constructs via biomaterial-based presentation of inflammatory cytokines may serve as a novel means of regulating MSC immunomodulatory paracrine secretion in vivo. Therefore, the objective of this research is to regulate human MSC immunomodulatory activity via the incorporation of immobilized-cytokine microparticles within 3D MSC spheroids.