Autoimmunity

Functionally defective germline variants of sialic acid acetylesterase in autoimmunity Surolia, I. et al. Nature 16 Jun 2010 (doi:10.1038/nature09115)

The enzyme sialic acid acetylesterase (SIAE) is a negative regulator of B cell receptor signalling, and mice with loss-of-function mutations in Siae develop an autoimmune syndrome. Previous genome-wide association studies did not detect an association between common variants of SIAE and autoimmune disease in humans. However, by identifying and analysing the function of a number of rare variants of SIAE, this study shows that rare functionally defective SIAE variants are enriched in patients with autoimmune diseases. When T cell lines were transfected with cDNAs encoding SIAE variants from either autoimmune or healthy subjects, the SIAE variants from the healthy controls encoded fully functional enzymes, but the variants identified in patients with autoimmune diseases encoded enzymes with a defect in catalytic activity or in secretion. These data show the importance of functional screening assays for identifying potential genetic risk factors for disease.

Tumour immunology

Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor Marigo, I. et al. Immunity 3 Jun 2010 (doi:10.1016/j.immuni.2010.05.010)

This study identifies C/EBPβ as a crucial transcriptional regulator of the myeloid-derived suppressor cells (MDSCs) that are induced by, and suppress the immune response to, tumour cells. Bronte and colleagues showed that they could generate mouse MDSCs in vitro — from bone marrow precursor cells cultured in the presence of granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) — that had similar phenotypical and functional properties to tumour-induced MDSCs. The exposure of mouse bone marrow cells to GM-CSF and IL-6 resulted in upregulation of C/EBPβ by these cells. The deletion of C/EBPβ in haematopoietic cells abrogated the T cell-suppressive activity of bone marrow-derived MDSCs in vitro and of splenic MDSCs in in vivo tumour models through decreased expression of arginase 1, nitric oxide synthase 2 and other components of the MDSC inhibitory machinery. C/EBPβ was also shown to control the immunoregulatory programme in human MDSCs.

T cells

Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Li, P. et al. Science 10 Jun 2010 (doi:10.1126/science.1188063)

Here the authors report that T cells can be reprogrammed as natural killer (NK)-like cells following deletion of B cell lymphoma 11b (Bcl11b). BCL-11b is highly expressed by thymocytes from the double negative 2 (DN2) stage of development and is crucial for T-lineage commitment. Bcl11b−/− DN1 and DN2 thymocytes that were cultured with OP9-DL1 stromal cells, which support T cell development, instead gave rise to cells expressing the NK cell marker NKp46 and not T cell genes Cd3 or T cell receptor β-chain (Tcrb). In addition, these cells — termed induced T-to-NK (ITNK) cells — killed tumour cells in vitro, and their morphology and expression profiles were more akin to activated NK cells than T cells. Even mature CD4+, CD8+ and γδ T cells with a conditional deletion of Bcl11b could be reprogrammed to be ITNK cells in vitro. Importantly, Bcl11b−/− thymocytes transferred into immunodeficient mice gave rise to ITNK cells that effectively prevented tumour metastasis in vivo.