Immune Engineering

Our current projects focus on T cells, key modulators of the adaptive immune response. Proper function of these cells is important for a robust immune response, while imbalances are at the core of many diseases including those based on autoimmunity. Tthe adaptive immune response is also being harnessed in a number of emerging cellular therapies.

We study T cell activation, an important step in shaping the immune response that is normally carried out by contact-mediated ommunication with an antigen presenting cell (APC). Numerous receptor-ligand interactions are formed within these cell-cell interfaces; in particular, binding of TCR/CD3, CD28, and LFA-1 on the T cell surface to peptide-loaded MHC (pMHC), CD80/CD86, and ICAM-1 on the APC form a basic set of interactions capable of producing cellular activation. Using micro-/nano-scale engineering and contemporary biophysical approaches, our research reveals new facets of T cell activation.

Spatially-resolved cellular signaling

A distinguishing feature of the T cell - APC interface leading to activation, a structured termed the Immune Synapse (IS), is that the myriad receptor-ligand interactions are organized into spatially complex patterns. It is increasingly clear that this microscale organization is part of the language of T cell - APC communication. Using micropattnered, multicomponent surfaces presenting ligands to CD3, CD28, and LFA-1, we established the following aspects of T cell costimulation and activation

• T cells are sensitive to the microscale organization of CD3 and CD28, with respect to location both within the cell-surface interface and each other.
• Mouse and human T cells respond to different aspects of this organization.
• These contrasting behaviors demonstrate spatially-resolved costimulation, and can be resolved through a reaction-diffusion mechanism involving the intermediate signaling kinase Lck.

Current studies focus on understanding the full impact of spatially resolved signaling in a variety of T cell subtypes and functions.

Biomechanics and rigidity sensing

T cell - APC contacts are also characterized by a highly dynamic cytoskeleton that drives the morphology and organization of these interfaces as well as larger functions including cell migration. Adapting techniques used to study cell mechanics in other cellular systems, we established some surprising aspects of T cell activation.

• Activation and expansion of CD4 and CD8 T cells is sensitive to the mechanical rigidity of a substate presenting ligands to CD3 and CD28.
• Mouse and human T cells exhibit contrasting responses to substrate rigidity..
• T cells generate signifcant traction forces through TCR/CD3.

Our current studies focus on understanding force generation through these non-integrin systems, as well as the physiological roles of mechanics in T cell function.

Immunotherapy

The ability to direct T cell activation and function may dramatically improve emerging cellular therapies based on adaptive immunity. We are applying the basic discoveries of micropatterned activation and biomechanics in this direction. In particular, we are using the ability of T cells to sense the mechanical rigidity of an activating substrate to enhance T cell expansion for clinical purposes.

 

Cellular Engineering

While T cells and immunology are the major focus of our current projects, the approaches we have developed have wide application in a range of other cellular and physiological systems. Two examples of these direction are included below.

Neural networks and development

The ability to direct outgrowth and establishment of connections between neurons will make possible new studies of neural plasticity computation. We used multicomponent patterns of polylysine, L1, and N-cadherin to control the somal position and extension of axons and dendrites, a major advance over that possible using previous-generation adhesive/non-adhesive patterns.

Coordination of epithelial cell function

The integrity of epithelial sheets to form barriers is dependent on cadherin signaling between cells. Using micropatterned surfaces, we demonstrated that engagement of integrin receptors can override cadherin function. Moreover, this was dependent on the mechanical rigidity of the substrate presenting an integrin ligand, fibronectin. Furthermore, this inhibition was observed in the tumorgenic MCF-7 cell line, but not in a model of normal epithelial cells.

 

Micro-/nano-engineered Systems

Our research captures complex micro-/nano-dynamics of the extracellular environment by focusing on the approaches, technologies, and theories associated with biomolecules. These include extracellular matrix proteins, lipid bilayer mimics of cellular membranes, and cell-cell communication proteins. Microfluidic systems provide additional capabilities for working with rare cells. Importantly, these are driven by core biological questions. Please contact us for additional information and opportunities.