A recent report in Science shows that PEST-domain-enriched tyrosine phosphatase (PEP) has a specific role in dampening the response of effector/memory T cells to T-cell receptor (TCR) stimulation. Like a teacher curbing the activity of a boisterous child, PEP can calm the response of experienced T cells to antigenic stimulation.

Pep-deficient mice had no obvious changes in lymphoid organs in early age, but developed splenomegaly and lymphadenopathy at ages greater than 6 months. This was due to an increased number of both CD4+ and CD8+ effector and memory T cells. The initial activation of wild-type and Pep-deficient naive T cells was similar; but 3–4 days after TCR stimulation, the Pep-deficient T cells were cycling faster with no apparent change in the rate of activation-induced cell death, giving them a growth advantage over wild-type T cells.

Pep is known to inhibit the TCR signal cascade by dephosphorylating a crucial regulatory tyrosine residue on the protein tyrosine kinase Lck. The authors showed in vitro that wild-type effector T cells restimulated through the TCR showed transient phosphorylation of this Lck tyrosine, whereas Pep-deficient T cells had sustained phosphorylation. For the Pep-deficient T cells, this resulted in prolonged and increased activation of downstream mitogen-activated protein kinases. When wild-type or Pep-deficient naive TCR-transgenic T cells were transferred to irradiated mice and then stimulated with specific antigen, the Pep-deficient T-cell populations expanded much faster, confirming that Pep has a similar inhibitory effect in vivo. The wild-type and Pep-deficient T-cell populations contracted at a similar rate after antigen challenge, again showing that Pep has no effect on cell death.

The increased number of effector/memory T cells in Pep-deficient mice was associated with the development of germinal centres in the spleen and Peyer's patches. This B-cell effect was shown to be partly a result of increased T-cell cooperation, although further studies of Pep in B cells are required. However, none of the mice had any evidence of autoantibodies or autoimmune disease, leading Chan and colleagues to suggest that lack of function of Pep could only act as an enhancer for autoimmunity by increasing T-cell clonal expansion after a primary initiating defect that affected self-tolerance. Pep might be one of the many checkpoints that our immune systems have developed to prevent an inappropriate, possibly self-reactive, response. By contrast, blocking the activity of Pep might enhance the response to vaccination.