There are two types of T lymphocytes, defined by the TCR variable proteins they employ, αβ and γδ. These two T lineages perform distinct functions in immune responses, but arise from a common immature precursor in the thymus. One of our major research interests is to elucidate the molecular processes that instruct the common precursor to adopt these alternate fates (i.e., αβ or γδ). We have found that the nature of the signal transduced by the TCR plays a key role, with transient TCR signals directing specification of the αβ fate, and sustained signals specifying the γδ fate. The signaling axis whose duration of activity is critical for fate specification is defined as: the extracellular regulated kinase (ERK), which induces early growth response (EGR) transcription factors, that transactive the inhibitor of DNA-binding 3 (ID3) target gene. Activation of the ERK-EGR-ID3 signaling axis specifies the alternative αβ and γδ fate through the graded reduction of the activity of E box DNA binding proteins (E proteins), which are critical regulators of lymphocyte development. Current efforts are focused on understanding this fate specification process by building global three-dimensional genomic regulatory networks assembled around E protein targets that are differentially occupied during fate specification. Because E proteins are well-known tumor suppressors, these efforts inform the etiology of leukemia as well as providing insights into the control of lymphoid development.

Our efforts to understand the molecular basis for αβ/γδ T lineage commitment, led us to identify an unusual molecular effector that plays a critical role in this process, the ribosomal protein, Rpl22. Ribosomal proteins (RP) have historically been viewed as supporting the ribosome’s ability to synthesize proteins; however, emerging evidence suggests that RP, many of which are RNA-binding proteins, can actually play critical regulatory roles that control both normal development and transformation. We have found this to be true for Rpl22. Its function is required for development of αβ lineage T cells, but is dispensable for development of γδ T cells. Moreover, it also regulates the emergence and behavior of hematopoietic stem cells and its loss appears to predispose hematopoietic progenitors, as well as cells in other tissues, to transformation. Of note, the function of Rpl22 as a tumor suppressor is antagonized by its highly homologous (73% identical) ribosomal protein paralog, Rpl22-Like1 (Like1), which promotes development and transformation. Accordingly, developmental outcomes and risk for transformation are controlled by the antagonistic balance of Rpl22 to Like1. These proteins do not appear to regulate development by altering the function of the ribosome, but instead appear to do so by functioning away from the ribosome, by binding particular RNA targets and controlling either their splicing or their translation. Efforts are ongoing to identify the collection of cellular targets through which they function as well as the molecular basis by which such similar proteins as Rpl22 and Like1 exert opposing functions. These studies should inform the etiology of a number of human cancers including acute lymphoblastic leukemia (ALL), myelodysplastic syndromes (MDS), and acute myelogenous leukemia (AML).

Many insights into the molecular control of lymphocyte development have resulted from defining the molecular basis for human immunodeficiencies, including servere combined immunodeficiency (SCID). Accordingly, we combine exome sequencing with screening of candidate genes in zebrafish to identify the gene mutations causing SCID. Using this approach, we have already defined a novel inheritance mechanism in SCID, termed uniparental disomy, where two copies of the same mutated, disease-causing allele were inherited from the mother. Moreover, this approach has also succeeded in identifying four novel SCID genes to date, whose functions are being explored. The role of these genes in the etiology or diagnosis of hematologic malignancies is also being explored. Collapse