Immune-associated nucleotide-binding proteins (IANs; also known as GIMAPs) constitute a family of GTP-binding proteins that are expressed by vertebrate immune cells. Until recently, little has been known about the function of these proteins. Now, a report in PLoS Biology shows that IAN1, IAN4 and IAN5 are crucial regulators of T-cell development in the thymus.

Developing T cells must pass through a series of checkpoints in the thymus. These include positive selection and negative selection, both of which depend on T-cell receptor (TCR) signalling and which result, respectively, in the survival of thymocytes that express a functional TCR and in the apoptotic death of thymocytes that strongly recognize ligand. Yousuke Takahama and colleagues set out to study the molecular mechanisms that regulate these selection processes. When examining the transcriptional profile of mouse thymocytes with various developmental characteristics, they found that the IAN-family proteins IAN1 and IAN4 are strongly upregulated by thymocytes that have undergone positive selection (that is, in cells that have progressed from the double-positive (DP) to the single-positive stage of development). They confirmed this finding using quantitative real-time PCR and additionally showed that IAN5 is also upregulated at this stage. However, enforced overexpression of IAN1 (but not IAN4 or IAN5) at an early stage of development (in double-negative thymocytes) was found to result in apoptosis at the DP stage, whereas inhibition of endogenous expression of IAN4 or IAN5 (but not IAN1) blocked thymocytes from reaching or progressing past the positive-selection checkpoint.

So, IAN-family members are novel TCR-responsive proteins that crucially and differentially regulate the survival and death of thymocytes. In subsequent experiments, IAN1 was found to associate selectively with the pro-apoptotic BCL-2 (B-cell lymphoma 2)-family member BAX (BCL-2-associated X protein), whereas IAN4 and IAN5 were found to associate with anti-apoptotic BCL-2-family members, including BCL-2 and BCL-XL. These findings indicate that IANs might exert their functions by relaying signals that regulate apoptosis from the TCR to BCL-2-family members, and this improves our understanding of the mechanism by which TCR signalling influences the fate of thymocytes.