How long a T cell lingers when sampling the surface of antigen-presenting cells (APCs) can determine how it responds. Recognition of cognate antigen through the T-cell receptor (TCR) sends a stop signal to the T cell, leading to reduced T-cell motility and prolonged engagement with the APC, a process that is necessary for efficient T-cell activation. The co-receptor CTLA4 (cytotoxic T-lymphocyte antigen 4) is known to regulate the threshold of signals during T-cell activation, but how it does so has been unclear. Now, Christopher Rudd and colleagues report in Science that CTLA4 overrides the TCR-mediated stop signal by increasing T-cell motility, thereby inhibiting T-cell activation.
Previously, this group had observed that CTLA4 promotes clustering of the integrin LFA1 (lymphocyte function-associated antigen 1) and cell adhesion, so they assessed whether CTLA4 also affects integrin-dependent motility. They found that pre-activated T cells that were treated with CTLA4-specific antibody had more movement on plates coated with the LFA1 ligand ICAM1 (intercellular adhesion molecule 1) than did untreated cells. Moreover, co-ligation of CTLA4 and CD3 on T cells reversed the arrest in movement that occurred when the T cells were exposed to CD3-specific antibody alone, indicating that CTLA4 ligation overrides the stop signal induced by TCR ligation.
In vivo imaging studies that tracked TCR-transgenic T cells responding to cognate antigen in the presence or absence of CTLA4 confirmed these in vitro observations. In the absence of antigen, CTLA4+ and CTLA4- T cells had similar patterns of movement in cervical lymph nodes, but in the presence of antigen, only the CTLA4- T cells showed the expected decrease in motility. By contrast, the motility of CTLA4+ T cells was increased or unaffected in the presence of antigen. Consistent with the failure to arrest in response to antigen, CTLA4+ T cells failed to form prolonged interactions with antigen-loaded APCs. This resulted in the CTLA4+ T cells producing considerably less interleukin-2 and proliferating less than the CTLA4- T cells.
So CTLA4 modulates the threshold of T-cell activation through a reverse-stop signalling mechanism. This mechanism might explain several aspects of co-receptor modulation of T-cell responses, including anergy induction, for which limited T-cell–APC interactions would reduce TCR-ligation events and responses to low-affinity autoantigens.