Excluding CD148 (red) from the synapse (green) keeps immune responses going.

A phosphatase gets squished out of the immunological synapse, thus preventing premature down-regulation of T cell immune responses, as demonstrated by Lin and Weiss on page 673.

The immune responses mounted when T cell receptors (TCRs) are engaged by antigens are initiated by tyrosine kinases and lead to cytokine production and T cell proliferation. One protein that is up-regulated in T cells during immune responses is CD148, a large transmembrane tyrosine phosphatase. CD148 has been shown to inhibit immune responses elicited when TCRs are stimulated with soluble anti-TCR antibodies. But Lin and Weiss now show that this down-regulation is normally delayed by the architecture of T cell contacts with antigen-presenting cells (APCs).

In the more biologically relevant context of B cells used as APCs, CD148 is still up-regulated after antigen presentation. But the authors find that it is excluded from the site of contact between the T cell and the APC (known as the immunological synapse), and thus fails to prevent the immune response.The bulky glycosylated extracellular domain of CD148 prevents it from entering the synapse, as the distance between the membranes of the T cell and APC is so small that proteins larger than four immunoglobulin domains are probably too large to enter. So CD148 cannot reach its substrates until the two cells disengage. In the experimental system, immune responses were inhibited only after 8 h of TCR stimulation. This timing gives T cells enough time to produce cytokines and begin proliferation programs, while preventing autoimmunity that might result from inappropriately prolonged responses. ▪