Celebrating T Cell Diversity

The duration of signals emanating from the T cell receptor (TCR) is finely regulated through several processes that control protein half-life, posttranslational modification of proteins, and the recruitment of inhibitory proteins. Egen and Allison have found that the inhibitory protein cytotoxic T lymphocyte antigen-4 (CTLA-4) is recruited to the immunological synapse, in direct proportion to the strength of the TCR signal, where it acts to extinguish TCR-dependent signals. CTLA-4 in T cells that were cultured with antigen-presenting cells (APCs) bearing agonistic or weakly agonistic peptides translocated to microtubule-organizing centers (MTOCs) close to the site of T cell-APC apposition. However, only T cells stimulated with the stronger agonist peptides led to the movement of CTLA-4 to the immune synapse at the plasma membrane. These data suggest that the location of CTLA-4 is dependent on the strength of the signal sent by the TCR. More important, the data suggest a reason why T cells would need a mechanism to inhibit TCR-dependent signaling after a strong signal is elicited. It is in an organism's best interest to have a widely varied immune response to a pathogen. Strong signals by a few T cells (that have high affinity for an antigen) could quickly lead to the proliferation of a very small subset of T cells at the expense of a diverse group of proliferating T cells with varying degrees of affinity for the antigen. Thus, a large number of T cells would recognize a very narrow repertoire of antigen--clearly a situation to the pathogen's advantage. However, by recruiting CTLA-4 to the immune synapse, the prolonged signaling that would be mediated by strongly agonistic antigens is attenuated, such that weakly stimulated T cells have an opportunity to proliferate and increase the diversity of T cell-mediated responses. J. G. Egen, J. P. Allison, Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16, 23-35 (2002). [Online Journal]