Research Program: Immunology
Professor, Department of Laboratory Medicine and Pathology, Center for Immunology

james024@umn.edu
612-625-1496 — office
612-625-5-1626 — lab
Preferred contact method: Email

Stephen Jameson received his Ph.D. in immunology from Cambridge University in Cambridge, England in the AFRC Institute of Animal Physiology & Genetics Research. He conducted his postdoctoral training with Dr. Nicholas R.J. Gascoigne at Scripps Clinic and Research Foundation, followed by work with Dr. Michael Bevan in the Department of Immunology at the University of Washington in Seattle. He was recruited to the Department of Laboratory Medicine and Pathology at the University of Minnesota in 1995.

Research Interests

The main focus of the Jameson lab is on T cell homeostasis. Maintenance of antigen specific T cells in the absence of foreign antigens is critical for their usefulness in immunity against pathogens and cancer cells. We study the role of various cytokines and of self peptide/MHC ligands in maintenance of both naive and memory T cells. A special focus of this work is on the T cell response to lymphopenia: When T cell numbers are low, residual naive T cells begin to proliferate and differentiate into memory-like T cells. This process, called homeostatic proliferation, may be useful if we can direct these memory-like cells into protective responses, but these cells could be dangerous if their reactivity toward self peptide/MHC ligands becomes overt autoimmunity. We have shown that various cytokines (including IL-7, IL-15 and IL-12) regulate homeostatic proliferation and are currently testing how availability of these cytokines, as well as exposure to self peptide/MHC ligands, influences the survival of the memory-like cells (also called "HP memory cells") and their functional response toward pathogens. Recent work showed that HP memory CD8 T cells have a similar protective capacity as "true" memory cells in controling a Listeria infection. However, we also made the surprising finding that residual CD4 T cells in the lymphopenic animal were needed for this protective function of the HP memory CD8 T cells. The role of the CD4 T cells is still unclear, but part of the mechanism involves TRAIL, the TNF-related apoptosis inducing ligand: We find that HP memory CD8 T cells which are deficient for the TRAIL gene no longer need CD4 help to control Listeria. Further studies are focused on the role of HP-memory cells in control of other pathogens (including vaccinia and LCMV) and on eradication of tumor cells. The latter is especially interesting, since TRAIL can induce apoptosis in some tumors, hence the "helpless" HP memory CD8 T cells (i.e. those generated with CD4 T cell help) may prove more effective against TRAIL-sensitive tumors, These studies relate to the clinical goal of reconstitution of the T cell compartment following chemo- and radio-therapy induced lymphopenia. More recently we have extended these studies into analysis of the homeostasis of Natural Killer (NK) cells. In this context we have pursued studies on the role of the cytokine IL-15 in regulation of T cell and NK cell development and homeostasis.

In addition, we are studying the role of the transcription factor KLF2 (also called LKLF) in T cell homeostasis. KLF2-/- animals show grossly normal thymic development, but severely reduced peripheral T cell populations, suggesting a critical role in T cell homeostasis. However, our recent studies suggest an entirely different function for KLF2. We found that KLF2-deficient thymocytes survive relatively normally in vitro and after adoptive transfer in vivo. However, their trafficking patterns are radically compromized: KLF2-/- T cells can enter (and survive in) the spleen, but are scarce in lymph nodes and blood. This correlates with a dramatic decline in expression of key trafficking molecules, including L-selectin, beta 7-integrin, and the lysophingolipid receptor S1P1. The S1P1 receptor is also critical for thymic egress and, accordingly, we find that KLF2-/- thymocytes cannot leave the thymus (which, in large part accounts for the peripheral T cell defect). Hence, KLF2 acts as a master regulator for T cell trafficking. KLF2 expression is very dynamic, being upregulated in mature naïve T cells, lost with T cell activation and reexpresed in memory T cells. Further studies are focussed on examining the role of KLF2 in regulating trafficking and reactivity following T cell activation and memory differentiation. In order to study this model further, we have recently acquired a conditional KLF2-knockout model system, which will allow for more precise control of gene targetting and eliminate the complications of the embyronic lethality found in conventional KLF-/- animals.

Selected Publications

Hamilton S.E., M.C. Wolkers, S.P Schoenberger and S.C. Jameson. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol. 2006;:475-481.

Carlson C.M., B.T. Endrizzi, J. Wu, X. Ding, M.A. Weinreich, E.R. Walsh, M.A. Wani, J.B. Lingrel, K.A. Hogquist and S.C. Jameson. Lung Kruppel-like factor (KLF2) regulates thymocyte and T cell migration. Nature. 2006 Jul 20;442(7100):299-302.