Abstract
T cell activation drives the protective immune response against pathogens, but is also critical for the development of pathological diseases in humans. Cytoskeletal changes are required for downstream functions in T cells, including proliferation, cytokine production, migration, spreading, and adhesion. Therefore, investigating the molecular mechanism of cytoskeletal changes is crucial for understanding the induction of T cell-driven immune responses and for developing therapies to treat immune disorders related to aberrant T cell activation. In this study, we used a plate-bound adhesion assay that incorporated near-infrared imaging technology to address how TCR signaling drives human T cell adhesion. Interestingly, we observed that T cells have weak adhesion early after TCR activation and that binding to the plate was significantly enhanced 30–60 minutes after receptor activation. This late stage of adhesion was mediated by actin polymerization but was surprisingly not dependent upon Src family kinase activity. By contrast, the non-catalytic functions of the kinases Fyn and Pyk2 were required for late stage human T cell adhesion. These data reveal a novel TCR-induced signaling pathway that controls cellular adhesion independent of the canonical TCR signaling cascade driven by tyrosine kinase activity.
Highlights
The engagement of the T cell antigen receptor (TCR) by a peptide-bound major histocompatibility complex is a crucial step in T cell activation and is accompanied by dynamic changes in the actin and microtubule cytoskeletons
Consistent with this idea, we recently found that proline-rich tyrosine kinase 2 (Pyk2) phosphorylation induced by soluble anti-TCR treatment correlates with two separate bursts of actin polymerization in human T cells [18]
We found that Jurkat cell and human activated peripheral blood T cells (hAPBTs) adhesion was significantly abrogated if these actin inhibitors were applied at this time (Figure 5A)
Summary
The engagement of the T cell antigen receptor (TCR) by a peptide-bound major histocompatibility complex is a crucial step in T cell activation and is accompanied by dynamic changes in the actin and microtubule cytoskeletons. Reorganization of the cytoskeleton is critical for T cell migration to secondary lymphoid organs and to sites of infection and inflammation [1,2]. These cytoskeletal rearrangements serve to enhance T cell adhesion to antigen presenting cells (APC) or infected target cells, a process that augments T cell effector functions [1,2]. Appropriate T cell responses are intricately linked to cytoskeleton reorganization. Understanding how TCR signals control cytoskeletal dynamics may allow one to therapeutically target dysfunctional T cell activation linked to several human diseases [6,7]
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