In the Roybal Lab we harness the tools of synthetic and chemical biology to enhance the therapeutic potential of engineered immune cells. We take a comprehensive approach to cellular engineering by developing new synthetic receptors, signal transduction cascades, and cellular response programs to enhance the safety and effectiveness of adoptive cell therapies. We also study the logic of natural cellular signaling systems, and the underlying principles of cellular communication and collective cell behavior during an immune response.

The Rutishauser Lab's goal is to characterize the regulation of human CD8+ T cell differentiation in response to viral infections and vaccination across the lifespan. Our lab is focused on three complimentary areas of study: 1) exploring the CD8+ T cell-intrinsic and -extrinsic mechanisms that regulate HIV-specific CD8+ T cell dysfunction/exhaustion; 2) defining the transcriptional and epigenetic basis for the altered T cell receptor-driven differentiation of fetal na������ve CD8+ T cells; 3) applying systems immunology approaches to assess longitudinal human immune responses to infection and vaccination using

The Saba Lab's research is focused on the role of sphingolipid metabolism in development, health and disease. We are particularly focused on the biology of the bioactive lipid metabolite sphingosine-1-phosphate (S1P) and the key enzyme responsible for its irreversible metabolism, S1P lyase, having cloned the latter from budding yeast years ago. We showed previously that a tiny population of dendritic cells harbor the S1P lyase activity that generates the S1P gradient needed for T cell egress. This discovery demonstrates a new role for thymic dendritic cells independent of their role in central tolerance. Although S1P lyase expression is higher in thymic epithelial cells (TEC) than in any other cell type of the body, this compartment of S1P lyase has no impact on T cell egress from the thymus, which raises important questions about the function of TEC S1P lyase. 2) S1P lyase in colitis and the gut microbiome. We showed previously that S1P lyase plays a critical role in reducing colitis risk through microRNA-mediated signaling involving STAT3 and NFkappaB inflammatory signaling hubs. We are currently exploring the impact of dietary and endogenous sphingolipids on the gut microbiome and dysbiosis. 3) S1P lyase and immunodeficiency. We recently reported a newly recognized inborn error of metabolism caused by inactivating mutations in SGPL1, which encodes human S1P lyase. We have named the condition sphingosine phosphate lyase insufficiency syndrome (SPLIS). There are many disease features, and mortality in the first decade is nearly 50%. Most if not all patients exhibit T cell lymphopenia, but some also have B and NKT cell deficiencies and low immunoglobulin levels. We are interested in fully characterizing the immunological status of SPLIS patients, leveraging their T cell lymphopenia in newborn screening strategies, and using immunological biomarkers including absolute lymphocyte count as disease biomarkers. The latter can be used to monitor responses to gene therapy and cofactor supplementation approaches we are developing to treat SPLIS patients.

The Sarwal Lab's research is based on computational approaches for analyzing public and lab developed genomic, proteomic, single cell sequencing, cyTOF, metabolomic and microbiome data and its applications to diagnosing renal and transplant injury as well as an emphasis on drug repositioning and new drug design. We focus on the application of novel, high throughput technologies to harness the entire complement of genes, proteins, metabolites and antibodies, to generate new hypotheses for unraveling the underlying mechanisms of complex human diseases. Much of the work focuses on human organ transplantation , and the research efforts of the lab have resulted in a new understanding of the role of B cells, microRNAs, non-HLA antibodies and proteins in acute graft rejection; the prediction of chronic rejection and recurrent FSGS and new onset diabetes after transplantation (NODAT), and the identification of new drugs and drug targets for organ transplant recipients. The goal is to improve the quality of care and life of the patient and to assist the physician in improved and targeted management of the patient, such that there is reduced recipient morbidity and improved quality of life.

The Scharschmidt Lab studies the cellular and molecular mechanisms mediating the adaptive immune response to skin commensal bacteria in order to elucidate the role of microbes in skin homeostasis and inflammatory skin disease. Research in our lab aims to: 1) define host pathways and immune cell populations that facilitate establishment of adaptive immune tolerance to skin commensals; 2) identify commensal-derived molecules that influence the development and function of adaptive immune cell populations in the skin; 3) elucidate how skin-specific structures, such as hair follicles, and the integrity of the skin barrier influence host-commensal dialogue in this tissue. Our scientific approach capitalizes on genetic manipulation of skin commensal bacteria, transcriptional profiling of both host and microbial cells and in vivo models to dissect the antigen-specific response to skin commensal organisms.

The Schjerven lab studies normal and malignant immune cell development with a focus on transcriptional regulation, and the molecular mechanisms underlying how mutations in key regulatory factors can cause disease. The transcription factor Ikaros, encoded by the IKZF1 gene, is a major focus of ongoing work. Due to the many roles of Ikaros in blood cell development and function, our lab has several diverse and complementary research projects.

The Sheppard Lab's research focuses on the in vivo roles of members of the integrin family, the biologic and therapeutic significance of integrin-mediated activation of transforming growth factor beta, and the molecular mechanisms underlying tissue fibrosis. One aim of the research is to identify new therapeutic targets to improve the treatment of common disorders including tissue fibrosis, cancer and asthma. The work begins with basic investigation of how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues and how these responses contribute to the development of common diseases.

The Shum Lab's research lies at the intersection of autoimmunity and pulmonary disease.

The Sil Lab studies the fungal pathogen Histoplasma capsulatum, which is a soil organism that can infect and colonize cells of the innate immune system after inhalation into mammals. Their research is driven by two key questions. First, how do cells sense temperature and make a developmental switch from the soil to the host program? They focus on temperature because it is a sufficient signal to recapitulate the morphologic switch bettheyen Histoplasma filaments (the soil form) and yeast (the host form) in culture. This question is critical to understanding the basic biology of Histoplasma as theyll as a number of closely related fungi such as Blastomyces, Coccidioides, and Paracoccidioides, each of which is a ubiquitous pathogen of immunocompetent hosts in endemic areas. In fact, one of the fascinating evolutionary questions about these environmental fungi is how regulatory circuits have evolved to link morphology and virulence programs with growth at host is be an entry point to broader studies of host-fungal interactions, since it will define critical developmental changes that promote the expression of virulence traits, as theyll as delineate molecular landmarks that will allow us to stage the interactions of the fungus with host cells. Second, how does H. capsulatum defy the innate immune response to take up residence, often permanent, in immunocompetent hosts? The past ten years have witnessed an exponential increase in their understanding of the innate immune response to microbes, and yet, in the case of fungi, their insight is rudimentary at best. Their studies explore the molecular communication at the host-pathogen interface bettheyen H. capsulatum and the macrophage. H. capsulatum displays extremely robust macrophage colonization, so it is currently the best fungal candidate to probe the Achilles' heel of these potheyrful innate immune cells and determine novel mechanisms of virulence that have evolved in eukaryotic pathogens.

The Ashouri lab is focused on understanding how aberrant immune cell signaling disrupts immune tolerance, resulting in autoimmune (AI) disease. We are particularly interested in T cell mechanisms that contribute to the onset of rheumatoid arthritis (RA), a debilitating disease affecting millions. A specific aim of the Ashouri lab is to identify antigen-activated T cells in RA in order to capture and profile arthritogenic clones and elucidate the earliest events in disease pathogenesis. Our work takes advantage of a specific reporter of T cell antigen receptor (TCR) signaling. Tracking the expression of this reporter of TCR signaling in murine and human T cells facilitates our ability to identify and study arthritis-causing T cells before and during RA disease development and addresses the following questions: 1) How are T cells that are relatively deficient TCR signaling able to mediate arthritis development? Our lab uses molecular and biochemical techniques to examine how chronic TCR signaling can enhance T cell sensitivity to cytokine signaling and its dysregulation in disease. 2) How are arthritis causing CD4 T cells initially triggered in disease and to what antigen do these T cells respond? We utilize multi-dimensional and high-throughput technologies including paired single-cell RNA and TCR-sequencing from mouse and human samples with significant potential to identify the TCR specificity, gene expression profile, and signaling networks of cells involved in antigen recognition in RA. Our model system provides a platform to track antigen-specific T cell responses in human diseases in which the inciting antigen is not known and could be broadly applied to other AI diseases, transplant rejection, cancer, and even checkpoint blockade.

The Sirota Lab's long-term research goal is to develop integrative computational methods and apply these approaches in the context of disease diagnostics and therapeutics. We are specifically interested in leveraging and integrating different types of omics and clinical data to better understand the role of the immune system in disease. We are developing computational methods and using them to understand immune tolerance in the context of autoimmune disease and non-response (pregnancy, organ transplant, cancer).

The Spitzer Lab is working to develop our understanding of how the immune system coordinates its responses across the organism with an emphasis on tumor immunology. We combine methods in experimental immunology and cancer biology with computation to understand the modes in which the immune system can respond to tumors and to rationally initiate curative immune responses against cancer.