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Nichols Lab: Research

The Nichols laboratory studies the genes and signaling pathways that regulate hematopoietic cell development and function, with the goal of understanding how defects in these pathways contribute to human diseases, such as immunodeficiency, autoimmunity and cancer. To address this goal, we work in a variety of model systems, including cell lines, genetically engineered mice and primary cells from control individuals and patients with immunodeficiency and cancer.

Pathogenesis of X-linked lymphoproliferative disease (XLP) and related immunodeficiencies

XLP is a rare, inherited immunodeficiency disorder associated with increased susceptibility to infection with Epstein-Barr virus (EBV), development of B-cell lymphomas, and progressive humoral immune defects. An early diagnosis is critical for patients and families due to the potentially life-threatening complications that can arise as the result of EBV infection.

We were among the first to identify the causative genetic defect in XLP, which occurs in the SH2D1A gene1. This gene encodes a protein known as SAP, which is expressed in and controls the functions of a variety of immune cell lineages including T lymphocytes, natural killer (NK) cells and invariant natural killer T (iNKT) cells. Our laboratory has examined how SAP regulates immune cell development and function and coordinates host immunity to EBV. Through these studies, we have defined key roles for SAP during natural killer cell cytotoxicity, CD4+ T cell “help” to B cells and invariant natural killer T (iNKT) cell ontogeny and activation2-5.

We are currently working to further elucidate the mechanisms through which SAP and its signaling partners control iNKT cell functions. We are also examining the molecular mechanisms that underlie other EBV-related immunodeficiencies6. These studies will allow us to identify how SH2D1A and other genetic mutations contribute to disease and provide clues for the development of therapeutic agents that target disrupted intracellular signaling pathways.

Development of invariant natural killer T (iNKT)-cell cancer immunotherapies

iNKT cells comprise an evolutionarily conserved subset of T lymphocytes, the majority of which express an invariant T cell receptor (TCR) that confers specificity for glycolipid antigens. Following engagement of the invariant TCR, iNKT cells rapidly secrete cytokines and up-regulate expression of co-stimulatory molecules. Via these properties, iNKTs efficiently mature dendritic cells (DCs) and they trans-activate the functions of NK, T and B cells. In addition to these immunostimulatory properties, we observe that iNKT cells exert potent lysis of tumor cells5,7. Based on their multiple anti-tumor functions, we are interested in developing novel iNKT cell-based immunotherapies that target pediatric cancers.

Figure 1: To test the direct anti-tumor effects of iNKT cells, immunodeficient mice lacking T, B, and NK cells were engrafted with purified murine iNKT cells. Four days later, mice received an injection of luciferase-expressing tumor cells. Tumor burden was monitored over time using bioluminescence imaging.

Figure 1: To test the direct anti-tumor effects of iNKT cells, immunodeficient mice lacking T, B, and NK cells were engrafted with purified murine iNKT cells. Four days later, mice received an injection of luciferase-expressing tumor cells. Tumor burden was monitored over time using bioluminescence imaging.

Towards this end, we are examining the receptors and signaling proteins that mediate iNKT cell:tumor cell interactions and developing novel methods with which to more effectively redirect iNKT cells to the site of tumors. The long-term goal of these studies is to develop a novel platform for cancer immunotherapy, where iNKT cells not only deliver the lethal hit but enhance the tumor-directed responses of other cells of the immune system.

Pathogenesis and treatment of hemophagocytic lymphohistiocytosis (HLH)

HLH represents a rare group of disorders characterized by the dysregulated activation of cytotoxic T cells and macrophages, which secrete high levels of pro-inflammatory cytokines. Current HLH therapies aim to suppress immune activation through the use of steroids and chemotherapeutic agents. Unfortunately, despite the use of these agents, up to 50% of HLH patients die from uncontrolled HLH.

We are using human HLH patient samples and murine HLH models to dissect the cell types, cytokines and signaling pathways that underlie the development of this life-threatening condition. We are also examining whether blocking specific signaling pathways will dampen pathogenic inflammatory responses, with the goal of developing improved, targeted therapies for patients with HLH8,9,10.

Browse all publications from Kim Nichols on PubMed

Functional analysis of cancer predisposition loci in childhood ALL

The transcription factor ETV6 is an important regulator of normal bone marrow hematopoiesis and thrombocyte development. Recently, we and others identified germline ETV6 variants associated with heritable predisposition to thrombocytopenia and B-acute lymphoblastic leukemia (B-ALL). Follow-up studies revealed that up to 1% of B-ALL patients harbor potentially damaging germline ETV6 variants. These findings implicate ETV6 as an important gene involved in B-leukemogenesis. Consistent with this notion, ETV6 is one of the genes most commonly mutated somatically in childhood B-ALL. Along with collaborators at St. Jude, we are investigating the consequences of germline ETV6 variants on normal hematopoiesis, B cell development and malignant transformation using cell-based assays and murine models.

Selected References

  1. Nichols KE, Harkin DP, Levitz S, Krainer M, Kolquist A, Gresko C, Bernard A, Ferguson M, Zuo L, Snyder E, Buckler AJ, Wise C, Ashley J, Lovett M, Valentice M, Look AT, Housman DE, Haber DA. Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome. Proceedings of the National Academy of Science 1998; 95:13765-13770.
  2. Tangye SG, Lanier LL, Phillips JH, Nichols KE. Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. Journal of Immunology 2000; 165:2932-2936.
  3. Cannons JL, Hill B, Yu LJ, Mijares L, Nichols KE, Antonellis A, Koretzky G, Gardner K, Schwartzberg PL. SAP modulates TH2 differentiation and PKC-theta-mediated activation of NF-kB1. Immunity, 2004; 21(5):693-706.
  4. Nichols KE, Hom J, Gong S-Y et al. Regulation of NKT cell development by SAP, the protein defective in XLP. Nature Medicine, 2005; 11(3):340-345.
  5. Das R, Bassiri H, Guan P et al. The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation. Blood, 2013; 121(17):3386-3395.
  6. Chaigne-Delalande B, Li F-Y, O’Connor GM et al. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science, 2013; 341(6142):186-191.7.
  7. Bassiri H, Das R, Guan P et al. iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo. Cancer Immunology Research, 2014; 2(1):59-69.
  8. Milone M, Tsai DE, Hodinka R et al. Treatment of primary Epstein-Barr virus infection in patients with X-Linked lymphoproliferative disease using B-cell-directed therapy. Blood, 2005; 105(3):994-996
  9. Chellapandian D, Das R, Zelley K et al. Treatment of Epstein-Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. British Journal of Haematology, 2013; 162(3):376-382.
  10. Teachey DT, Rheingold SR, Maude SL et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood, 2013; 121(26):5154-5157.
  11. Topka S, Vijai J, Walsh MF, Jacobs L, Maria A, Villano D, Gaddam P, Wu G, McGee RB, Quinn E, Inaba H, Hartford C, Pui CH, Pappo A, Edmonson M, Zhang MY, Stepensky P, Steinherz P, Schrader K, Lincoln A, Bussel J, Lipkin SM, Goldgur Y, Harit M, Stadler ZK, Mullighan C, Weintraub M, Shimamura A, Zhang J, Downing JR, Nichols KE, Offit K. Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genet. 11(6):e1005262, 2015. doi:10.1371/journal.pgen.1005262. PMID: 26102509.
  12. Moriyama T, Metzger ML, Wu G, Nishii R, Qian M, Devidas M, Yang W, Cheng C, Cao X, Quinn E, Raimondi S, Gastier-Foster JM, Raetz E, Larsen E, Martin PL, Bowman WP, Winick N, Komada Y, Wang S, Edmonson M, Xu H, Mardis E, Fulton R, Pui CH, Mullighan C, Evans WE, Zhang J, Hunger SP, Relling MV, Nichols KE, Loh ML, Yang JJ. Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study. Lancet Oncol. 16(16):1659-66, 2015. doi: 10.1016/S1470-2045(15)00369-1. PMID: 26522332.