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Early T cell activation in the lymphoid milieu

  • Author(s): Friedman, Rachel Sharon
  • Advisor(s): Krummel, Matthew F
  • et al.
Abstract

Our goals were to elucidate the dynamics of naïve T cell activation in its native environment, the secondary lymphoid organs, and determine the effects of the lymphoid milieu on this process.

T cell activation in vivo occurs in a lymphoid environment that concurrently presents chemotactic signals and T cell receptor (TCR) signals. We show that T cell recognition of T zone chemokines such as CCL21 occurs when they are bound to the surface of antigen presenting cells (APCs), and that CCL21 is bound to the surface of lymph node dendritic cells. Contact with APCs bearing chemokines costimulated T cells via a novel two-step contact mechanism. Upon T cell contact with the chemokine-bearing APC, a chemokine-mediated 'tethered' adhesion was established. The formation of these tethers superceded TCR-signaling and immunological synapse formation. Instead, they captured the T cell in a state in which its leading edge projected and retracted until it found a suitable new surface. Establishment of this contact enhanced T cell sensitivity to antigen because antigen-dependent conjugate formation was more robust during subsequent antigen stimulation, even when the chemokine and antigen were presented on separate APCs. Thus, a 'trans' costimulation via chemokine-initiated tethering and priming allows microenvironmental cues to modulate T cell reactivity.

To examine the dynamics of TCR behavior during naïve T cells activation, we made a TCR-GFP transgenic mouse expressing an EGFP tagged OT-I TCR. When interacting with antigen-bearing mature dendritic cells, naïve T cells showed several behaviors, including TCR polarization to the immunological synapse followed by rapid TCR internalization into vesicles through the cSMAC, abrogation of the synapse upon TCR internalization, and translocation of internalized pools of TCR to the cSMAC. These data may suggest that during short T cell-DC interactions, TCR internalization provides a cue for naïve T cells to move on to another APC, and upon subsequent stimulus, internalized pools of TCR can be delivered to the site of the immunological synapse. Rapid antigen-specific TCR polarization was seen through two-photon microscopy following the addition of antigen to lymph nodes, indicating that T cells are able to rapidly engage APCs in vivo, without previous antigen stimulus.

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