Dr Sudha Kumari

MIT

Cytoskeletal networks dictate migratory arrests in lymphocytes

T lymphocytes (T cells) migrate throughout the body scanning for presence of disease. Upon encountering antigen displayed on antigen presenting cells (APCs), T cells immediately arrest and form intercellular junctions with APCs termed immunological synapses, which mediate crucial exchange of antigenic information. Optimal T cell activation during an immune response requires T cells to prolong their synaptic contacts with APCs. However, following activation, such synapses must eventually disengage to allow T cells to execute their immunological functions elsewhere in the body. Therefore, proper regulation of T cell motility states is a crucial requirement for a healthy immune response. Yet, little is known about the cellular mechanisms by which highly migratory T cells achieve rapid transitions in motility states. To answer this outstanding question, we first reformulate it by asking how T cells make a decision between sustaining or breaking the symmetry of the immunological synapse – a choice that fundamentally dictates whether a T cell remains with the APC, or migrates onwards. Using freshly isolated primary T cells activated using natural and synthetic APCs in combination with super resolution and ultrastructural microscopy techniques as well as computational simulations, we find that cytoskeletal organization is the primary determinant and regulator of synapse symmetry. Antigen encounter triggers rapid cytoskeletal rearrangement that generates as well as symmetrizes in-plane cytoskeletal tension preventing symmetry breaking. Once a T cell is activated, downregulation of a cytoskeletal regulatory protein creates a rapid switch in tension allowing symmetry breaking, synapse disengagement and resumption of T cell motility. Surprisingly, the sustenance of synaptic symmetry does not require integrin activation and is independent of APC stiffness. In my seminar, I will also discuss the cytoskeletal architectures and mechanisms that underlie T cell-APC synapse interface stability and regulate its symmetry regardless of the APC’s integrin composition and stiffness. I will also highlight distinctions and similarities between immunological synapses and other transient cell-cell contacts found in biology.

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