Keli Holzapfel

Keli HolzapfelDepartment

Center for Immunology, Department of Laboratory Medicine and Pathology

Program

Molecular, Cellular, Developmental Biology and Genetics (MCDB&G); Joint Degree Program in Law, Health and the Life Sciences

Mentor

Kristin Hogquist, PhD

Project description

I am a combined degree (JD/PhD) student in the MCDB&G program, doing my thesis research in the lab of Kris Hogquist in the Center for Immunology, on invariant Natural Killer T (iNKT) cells. iNKT cells play a vital role in regulating the kinetics, extent, and characteristics of an immunological response. I have two projects that seek to understand the development and activation of these cells. My first project examines antigen-dependent versus antigen-independent activation of iNKT cells during infections. Previous reports in the literature suggest that iNKT cells respond to endogenous glycosphingolipids during certain bacterial infections. One example of this is with Salmonella infection in which iNKT cell activation is reported to be dependent on CD1d and suggests a role for iNKT cell recognition of endogenous lipid antigen. In this model, it is thought that inflammatory cytokines induce antigen presenting cells to present a self-lipid that directly activates iNKT through the antigen receptor. In order to determine if iNKT cells are activated by antigen receptor recognition or only through inflammatory cytokines during bacterial infection, we have analyzed iNKT activation during infection with Salmonella typhimurium. To test for antigen receptor recognition, we infected Nur77GFP BAC transgenic mice, which express GFP in T cells in response to antigen receptor stimulation but not inflammatory signals. My other project involves the culturing and characterization of NKT cells derived from hematopoietic stem cells (HSCs), which have great therapeutic potential for the treatment of many different diseases. In my experiments, I am using the OP9-DL1 to derive iNKT cells. This cell line expresses a ligand that allows for HSC differentiation into a double positive thymocyte pool from which a small population of iNKT cells are selected. I am using different cytokines to optimize the conditions for iNKT cell selection, and then examining the function and characteristics of these HSC-derived iNKT cells. Ultimately, these experiments will aid in the development of iNKT-based therapies that take advantage of an iNKT cell’s ability to influence other immune cells in order to artificially orchestrate an immune response.

Publications

Lee, Y.J., Holzapfel, K.L., Zhu, J., Jameson, S.C. and Hogquist, K.A. A novel iNKT cell subset produces IL-4 in the steady state and modulates immunity. (manuscript submitted)

Moran, A.E., Holzapfel, K.L., Xing, Y., Cunningham, N.R., Maltzman, J.S., Punt, J. and Hogquist, K.A. 2011. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208: 1279-1289.