Immunology Graduate Group

Jordan Orange, M.D., Ph.D.
Assistant Professor of Pediatrics,
University of Pennsylvania School of Medicine
Department of Pediatrics

Address: 3615 Civic Center Blvd.
ARC 1216F
Philadelphia PA 19104
Office Phone:  267-426-5622
Lab Phone: 215-590-6195
Fax: 267-426-5727
Email:  orange@mail.med.upenn.edu

Website: www.orangelab.org

Education:
M.D., Brown University
Ph.D., Brown University
A.B., Brown University

Research Interests
Natural killer cell biology and the innate immunological synapse

Research Summary

Natural killer (NK) cells are lymphocytes critical to host defense. They do not undergo genetic recombination to attain specificity and therefore are part of the innate immune system. NK cells mediate cytotoxicity and produce cytokines, but these functions can be blocked by ligation of inhibitory receptors recognizing MHC molecules. The foundations of NK cell activities and regulation lie at the interface between NK cells and target cells. Molecules accumulate in this region and result in a dynamic structure called the NK cell immunologic synapse (NKIS).

My laboratory is investigating the formation and function of the NKIS. We have shown that the activating NKIS is actin-dependent compared to the inhibitory NKIS, which is actin-independent. We have also identified sequential steps required for creation of the activating NKIS and are pursuing the underlying circuitry in both time and space. Events critical in forming the activating NKIS are further being explored as targets for inhibitory signals generated by the inhibitory NKIS. We are additionally investigating events at the NKIS that result in activation-induced transcriptional regulation and how they ultimately affect cytotoxic function. My work is facilitated by the use of cells from individuals having gene mutations that specifically impair immunologic and or cellular processes. Understanding these basic cellular events with an appreciation for their pathobiological context will provide insight into the role of NK cells in maintenance of health and presents unique opportunities to comprehend intracellular interactions and innate immunity.

Recent Publications

Orange, J.S., Brodeur, S.R., Jain, A., Bonilla, F.A., Schneider, L.C., Kretschmer, R., Nurko, S., Rasmussen, W.L., Koehler, J.R., Gellis, S.E., Fergusson, B.M., Strominger, J.L., Zonnana, J., Ramesh, N., Ballas, Z.K. and Geha, R.S. Deficiency of natural cytotoxicity in patients with IKK?/NEMO mutations. 2002. J. Clin. Invest. 109:1501-1509.

Orange, J.S. Human Natural Killer Cell Deficiencies and Susceptibility to Infection. 2002, Microbes Infect. 4:1545-1558.

Orange, J.S., Ramesh, N. Remold-O'Donnell, E., Sasahara, Y., Koopman, L., Byrne, M., Bonilla, F.A., Rosen, F.S., Geha, R.S., and Strominger, J.L. Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell activating immunologic synapses. Proc Nat. Acad Sci. USA. 2002. 99: 11351-11356.

Orange, J.S., Fassett, M., Koopman, L.A., Boyson, J.E., and Strominger, J.L. Viral Evasion of Natural Killer cells. 2002, Nature Immunol. 3:1006-1012.

Levy, O., Orange, J.S., Hibberd, P., Steinberg, S., LaRussa, P., Weinberg, A., Wilson, B.S., Shaulov, A., Fleischer, G., Geha, R.S., Bonilla, F.A., Exley, M. Disseminated Varicella infection due to vaccine (Oka) strain Varicella zoster virus in a patient with a novel deficiency in natural killer T cells. 2003, J. Infect. Dis. 188:948-953

Orange, J.S., Geha, R.S., and Bonilla, F.A. Acute chylothorax in children: selective retention of memory T cells and natural killer cells. 2003, J. Pediatr. 143:243-249

Koopman, L.A., Kopcow, H.D., Rybalov, B., Boyson, J.E., Orange, J.S., Schatz, F., Masch, R., Lockwood, C.J., Schacter, A.D., Park, P.J., Strominger, J.L. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. 2003, J. Exp. Med. 198:1201-1212.

Orange, J.S., Harris, K.E., Andzelm, M.M., Valter, M.M., Geha, R.S., and Strominger, J.L., The activating natural killer cell immunologic synapse is formed in distinct stages. 2003, Proc. Natl. Acad. Sci. 100:14151-14156.

A human natural killer cell is shown conjugated to a tumor cell. The accumulation of actin filaments (blue) and CD2 (red) at the immunologic synapse can be seen preceding the localization of the cytolytic molecule perforin (green).  

 

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