TCR signaling, necessary for normal T cell development and T cell function, proceeds through the induction of protein phosphorylation of downstream molecules, including the membrane-anchored adaptor LAT. LAT, a substrate of the ZAP70 tyrosine kinase, is phosphorylated on multiple tyrosines that serve as docking sites for the recruitment of several effector molecules, including PLCγ1, Gads/SLP-76, and Grb2/SOS, that are responsible for induced increase in Ca2+ and activation of the Ras/MAPK pathway.

Human immune deficiencies often reveal unexpected functions or highlight differences between human and mouse immune systems. In this issue, Keller et al. describe a family with three children that are homozygous for LAT mutations leading to premature LAT truncation, eliminating all of its known tyrosine phosphorylation sites. The clinical phenotypes of these patients were heterogeneous, characterized by aspects of immune deficiency and autoimmunity. Most noteworthy, some T cells developed in these patients. Interestingly, stimulation of the TCR on the T cells of the one patient that could be studied resulted in a substantial calcium increase and evidence of NF-κB activation but no Erk activation.

The development of some T cells in these patients is surprising, as are the signaling studies. Germline deletion of LAT in mice results in profound early thymocyte developmental arrest, resulting in complete absence of peripheral T cells. It is possible that some LAT-related molecule might compensate for the loss of LAT function in the human, but efforts to identify such molecules were not productive. Alternatively, the truncated LAT protein might not represent a complete loss-of-function mutant. However, the authors examined the function of the truncated mutant in a LAT-deficient Jurkat T cell where they confirmed that the mutant LAT molecule did not support PLCγ1 phosphorylation, Ca2+ increase, Erk phosphorylation, or CD69 induction. Thus, the authors’ findings with the mutant LAT provided the expected phenotype based on previous studies with LAT mutants in Jurkat and in mice.

So what accounts for the preserved signaling and somewhat preserved T cell development in the patient cells? There is no clear explanation. The mouse and Jurkat systems may differ from signaling systems in human T cells. Most puzzling, however, is the observation that increases in Ca2+ and Erk, which are usually coupled and downstream of PLCγ1 activity, are discordant here. These studies would suggest a pathway leading to calcium increase that is dissociated from the activation of PLCγ1 operates in human but not in mouse or Jurkat T cells. These studies present an interesting and puzzling set of observations that await explanation.


, et al
J. Exp. Med.