T cell
function is dependent on contact with APCs. Contact leads to antigen
presentation by an APC to a T cell and the formation of a synapse. The synapse
plays a key role in T cell activation and its formation and stability are
tightly regulated.
Neuroserpin is an axonally secreted serine protease inhibitor
or serpin which inhibits trypsin-like serine proteases. Neuroserpin most effectively
inhibits tissue plasminogen activator (tPA). Changes in the neuroserpin:tPA
balance in the brain may underlie neuroserpin’s effects on behaviour in
transgenic mice overexpressing neuroserpin by regulating proteolytic cleavage
at the synapse to modify synaptic stability and/or neuronal connectivity.
We report that neuroserpin is expressed in human T cell populations and
partially co-localizes with a TGN38/LFA-1-positive vesicle population. TGN38
has been proposed as a cargo receptor involved in the secretion of proteins
which function in cell adhesion or migration. Using flow cytometry we found
evidence for secretion of neuroserpin following T cell activation with the
phorbol ester PMA and ionophore ionomycin. Activation of T cells with CD3/CD28
antibody-coated beads or a B cell line pulsed with the cognate peptide to
specific T cell clones led to polarization of neuroserpin to the synapse.
Activation of T cells with CD3/CD28 antibodies also resulted in rapid transient
upregulation of tPA mRNA and a delayed downregulation of neuroserpin
transcripts. Our data support a model of activation-mediated control of proteolytic
activity at the immunological synapse with active tPA either directly cleaving
synaptic proteins to modulate their function or catalysing the conversion of
the inactive zymogen plasminogen to active plasmin, which is known to process a
number of proteins that regulate T cell and APC function.