A framework for highly multiplexed dextramer mapping and prediction of T cell receptor sequences to antigen specificity.

T cell receptor (TCR) antigen-specific recognition is essential for the adaptive immune system. However, building a TCR-antigen interaction map has been challenging due to the staggering diversity of TCRs and antigens. Accordingly, highly multiplexed dextramer-TCR binding assays have been recently developed, but the utility of the ensuing large datasets is limited by the lack of robust computational methods for normalization and interpretation. Here, we present a computational framework comprising a novel method, ICON (Integrative COntext-specific Normalization), for identifying reliable TCR-pMHC (peptide-major histocompatibility complex) interactions and a neural network-based classifier TCRAI that outperforms other state-of-the-art methods for TCR-antigen specificity prediction. We further demonstrated that by combining ICON and TCRAI, we are able to discover novel subgroups of TCRs that bind to a given pMHC via different mechanisms. Our framework facilitates the identification and understanding of TCR-antigen-specific interactions for basic immunological research and clinical immune monitoring

The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins

Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers