A new study by Martin et al. reports that deficiency in CTP synthase 1 (CTPS1), one of two CTP synthases involved in the de novo synthesis pathway of the nucleotide triphosphate CTP, impairs T and B cell function, resulting in impaired immunity against infection and cancer (Nature 510, 51288–51292, 2014).

The researchers carried out whole-exome sequencing on DNA from three of eight patients (from five families) who experienced frequent viral and bacterial infections—and lymphoma in two cases—which is suggestive of a defect in adaptive immunity. They found all patients to be homozygous for a point mutation in CTPS1 that resulted in loss of exon 18. The mutation inhibited expression of CTPS1 in patients' cells.

Martin et al. found that CTPS1 is strongly upregulated upon T cell or B cell stimulation in vitro. Moreover, CTPS1-deficient T cells had impaired T cell receptor–triggered cell proliferation and DNA and RNA synthesis. CTPS1-deficient B cell proliferation after stimulation was also reduced. T cell proliferation could be restored by supplementing cells with CTP or cytidine. Notably, the presence of CTPS2 did not compensate for the lack of functional CTPS1 in patient T cells, although it may act redundantly with CTPS1 in nonimmune cells, given the absence of other clinical phenotypes in the patients.

The authors suggest that this selective dependence of T cells on CTPS1 might be exploited to develop a more targeted immunosuppressant.