Description of Research Expertise

Key Words:

Signal transduction, invariant natural killer T cells, neutrophils, immunodeficiency, X-linked lymphoproliferative disease, hemophagocytic lymphohistiocytosis.

Research Interests:

Immunobiology with a focus on the development and activation of invariant natural killer T (iNKT) cells and neutrophils (polymorphonuclear cells; PMN).

Description of Research:

Our laboratory is interested in the study of immune cells and their roles in maintaining health and mediating disease. In particular, we are examining how specific signaling molecules regulate the development and activation of invariant natural killer T (iNKT) cells and neutrophils (PMN). We use tissue culture systems and mice deficient in the expression of these signaling proteins, or animals expressing mutant proteins, to dissect their functions within these lineages. Our studies are relevant to the understanding of normal immune resopnses as well as the development and treatment of inflammatory diseases, immunodeficiency and cancer. Within this theme of innate immune cell biology/signal transduction, the lab has three major areas of research investigation:

1) Study of Signaling Lymphocytic Activation Molecule [SLAM]-associated protein (SAP), a cytoplasmic adaptor that regulates numerous aspects of the normal immune response.
We were among the first to demonstrate that mutations in the gene encoding SAP cause X-linked lymphoproliferative disease (XLP), an often life-threatening primary immunodeficiency marked by increased susceptibility to Epstein Barr virus infection, development of lymphoma and humoral immune defects. Since this initial observation, our lab has been interested in understanding how loss of SAP function impairs antiviral and antitumor immunity. Recently, we observed that expression of SAP is critical for the development of invariant natural killer T (NKT) cells, an innate-type lymphocyte sublineage that protects against infections and certain cancers, mediates graft tolerance and protects against autoimmune disease. Ongoing studies aim to dissect how SAP regulates NKT cell ontogeny and to determine whether SAP plays a role in mature NKT cell activation.

2) Mechanisms controlling NKT cell cytotoxic responses. Many studies implicate NKT cells as potent mediators of antitumor immune surveillance. Existing data suggest that the protective properties of NKT cells may be due to their production of pro-inflammatory cytokines that then activate other cytotoxic effectors, such as natural killer (NK) cells and CD8+ T cells. Our data reveal that in addition to producing pro-inflammatory cytokines, NKT cells exhibit direct cytolytic responses towards tumor target cells. In our in vitro tumor model system, NKT cell-mediated killing of targets is T cell receptor-dependent and requires tumor cell CD1-dependent antigen presentation. Based on these findings, we are now further characterizing the molecular events that control NKT cell killing and lytic synapse formation and determining whether NKT cells traffic to and directly kill tumor cells in vivo. Collectively, these studies will define how NKT cells destroy malignant cells and suggest ways to manipulate their cytolytic functions to enhance the treatment of patients with malignancy and specific types of infection.

3) Regulation of PMN functions by the Src homology 2 domain containing Leukocyte Phosphoprotein of 76 kD (SLP-76) and its associated partner proteins. PMN are among the first cells to respond to invading pathogens. While their antibacterial properties are critical for host protection, the aberrant activation of PMN leads to tissue destruction and contibrutes to organ damage in autoimmune disease. To better understand PMN functions and to develop novel therapies for these and related diseases, we are examining the mechanisms that govern PMN activation. Previously, we demonstrated that the adaptor molecule SLP-76 is critical for promoting in vitro PMN degranulation and production of reactive oxygen intermediates. Furthermore, loss of SLP-76, or mutation of its N-terminal domain, protects against leukocyte infiltration and development of joint destruction normally evident in a live animal model of serum-induced arthritis. These are the first data to demonstrate a role for SLP-76 in PMN activation and suggest that further elucidation of the SLP-76-dependent biochemical pathways may provide important insights into PMN biology.

Rotation projects are available in all areas.

Laboratory personnel:

Kim Nichols, MD - PI
Rupali Das, PhD – research associate
Shamim Ahmad, PhD – postdoctoral fellow
Hamid Bassiri, MD, PhD – postdoctoral fellow
Khurram Shafique, MD – visiting scientist
Peng Guan, BS – research specialist
Joyce Liu – summer undergraduate student

Selected recent publications:

Milone M, Tsai DE, Hodinka R, Silverman LB, Stadtmauer EA, Malbran A, Wasik M, Nichols KE. Use of B-cell directed therapy to treat primary Epstein-Barr virus (EBV) infection in patients with X-Linked Lymphoproliferative disease (XLP). Blood, 2005; 105(3):994-996.

Nichols KE, Hom J, Gong S-Y, Ganguly A, Ma C, Cannons J, Tangye SG, Schwartzberg PL, Koretzky GA, Stein PL. Regulation of NKT cell development by SAP, the protein defective in X-linked lymphoproliferative disease. Nature Medicine, 2005; 11(3):340-345.

Nunez-Cruz S, Yeo WCJ, Rothman J, Ojha P, Bassiri H, Juntilla M, Davidson D, Veillette A, Koretzky GA, Nichols KE. Differential requirement for the SAP-Fyn interaction during NKT cell development and activation. Journal of Immunology, 2008; 181(4):2311-2320.

Cen O, Guzman L, Jain J, Bassiri H, Nichols KE, Stain PL. The adaptor molecule SAP regulates IFNg and IL-4 production in Va14 transgenic NK cells via effects on GATA-3 and T-bet expression. Journal of Immunology, 2009; 182(3):1370-1378.

Snow AL, Marsh R, Krummey SM, Roehrs P, Young LR, Kejian Zhang, Jack van Hoff, Dhar D, Nichols KE, Filipovich AH, Su HC, Bleesing JJ, Lenardo MJ. SAP deficiency impairs NTB-A-dependent, restimulation-induced apoptosis of T cells from X-linked lymphoproliferative disease patients, Journal of Clinical Investigation, 2009; 119(10):2976-2984.

Lenox LE, Kambayashi T, Okamura M, Prieto C, Sauer K, Bunte R, Jordan MS, Koretzky GA, Nichols KE. Mutation of tyrosine 145 of lymphocyte cytosolic protein (Lcp; SLP-76) protects mice from anaphylaxis and arthritis. Journal of Allergy and Clinical Immunology, 2009; 124(5):1088-1098.

Booth C, Gilmour KC, Gennery AR, Slatter MA, Chapel H, Heath P, Steward C, Smith O, O’Meara A, Kerrigan H, Mahlaoui N, Cavazzana-Calvo M, Pachlopnick-Schmid J, Albert M, Notheis G, Reiber N, Strahm B, Ritterbusch H, Lankester A, Hartwig NG, Meyls I, Plebani A, Soresina A, Finocchi A, Pignata C, Broccoletti T, Bonanomi S, Peters C, Kalwak K, Pasic C, Sedlacek P, Jazbec J, Kanegane H, Terui K, Nichols KE, Hanson IC, Kapoor N, Haddad E, Cowan M, Choo S, Ip W, Arkwright P, Gaspar HB. X-linked Lymphoproliferative Disease due to SAP/SH2D1A deficiency: A Multicentre Study on the manifestations, management and outcome of the disease. Blood, 2011; 117(1):53-62.

Rezaei N, Mahmoudi E, Aghamohammadi A, Das R, Nichols KE. X-Linked Lymphoproliferative Syndrome: A genetic condition typified by the triad of infection, immunodeficiency and lymphoma. British Journal of Hematology, 2011; 152(1):13-30.

Das R, Sant’Angelo D, Nichols KE. Transcriptional mechanisms controlling invariant natural killer T cell development. Immunological Reviews, 2010; 238(1): 195-215.

Jyonouchi S, Abraham V, Orange JS, Spergel JM, Gober L, Dudek E, Saltzman R, Nichols KE*, Cianferoni A. Invariant natural killer T cells from food allergic versus non-allergic children exhibit differential responsiveness to milk derived sphingomyelin. Journal of Allergy and Clinical Immunology, 2011; in press. *Co-corresponding author.

Description of Clinical Expertise

Dr. Nichols is a pediatric oncologist with clinical interests in cancer genetics and the treatment of children with lymphoma, EBV-related lymphoproliferative disorders, Langerhans cell histiocytosis and the hemophagocytic lymphohistiocytoses.