Stephen Jameson, PhD

Professor and Chairman's Fund Professorship in Experimental Pathology, Department of Laboratory Medicine and Pathology

Stephen Jameson

Contact Info

james024@umn.edu

Office Phone 612-625-1496

Fax 612-625-2199

Lab Phone 612-625-1626

Mailing Address:
WMBB
2641D
2101 6th St. SE
Minneapolis, MN 55455

Scripps Clinic and Research Foundation, CA (Immunology), 1990

University of Washington (Immunology), 1995

PhD, Cambridge University, England (Immunology), 1988

BSci, Bristol University, England (Cellular Pathology), 1984

Summary

Dr. Jameson studies the factors that regulate the survival and activation of mature T-cells in the peripheral lymphoid system that engage in immune responses. An area of his current research interest is learning how vaccines work in the T-cell context. In experimental studies in mice, he and his colleagues applied vaccines to skin to see whether epicutaneous application was sufficient to generate an effective memory CD8 T-cell response that would be protective against bacterial and viral infection. Though somewhat less protective than injected or oral vaccine, epicutaneous immunization using adhesive bandages could potentially be used in developing countries due to the ease of application.

Awards & Recognition

  • University of Minnesota, Academy of Excellence in Health Research 2014
  • Frederick W. Alt Award for New Discoveries in Immunology, Cancer Research Institute, 2011
  • Special Fellowship, The Leukemia Society of America, 1993 - 1996
  • Postdoctoral Fellowship, Cancer Research Institute, 1989 - 1991

Professional Associations

University of Minnesota Cancer Center, 1996 - present

Research

Research Summary/Interests

The T-cell component of the adaptive immune system is proving to be highly complex, with many T-cell subcategories being identified as investigative tools such as flow cytometry and transgenic technologies become more sophisticated. Flow cytometry, for example, now allows researchers to identify and isolate T-cells with tens or even hundreds of characteristics compared to just a handful two decades ago. These technological advances have enabled Jameson’s team to identify subsets of memory T-cells with different functions including those most protective against disease. One subset of memory T-cells in the circulation appears early in the immune response but these cells tend to die off (short-lived effector cells); Jameson’s group characterized a related subset that survive for much longer (long-lived effector cells). These memory T-cells, which were thought to be relatively unimportant in immune response, turn out to be the best among memory T-cell populations for protecting against viral and bacterial infections in experimental animals. Jameson’s team is exploring why these long-lived effector cells possess a functional advantage over other memory T-cells.

In a companion line of inquiry, Jameson and his colleagues have identified another subset of memory T-cells produced by an immune response that take up residence in organs and tissues such as the lung, liver, and skin and not in the circulatory system. Recently, they have found that a transcription factor called Kruppel-like factor 2 (KLF-2) acts as a kind of toggle switch in these cells that allows them to migrate out of body tissues when the switch is turned on and keeps them in place when the switch is turned off. These “resident” memory T-cells provide a valuable protective function because many infections are localized to barrier and mucosal surfaces where these cells reside, monitor threats, and recruit additional support if necessary.

Identifying the molecular signals that guide the development and behavior of long-term effector T-cells and resident memory T-cells will guide future research in Jameson’s laboratory. A comprehensive understanding of localized memory T-cells is key to developing novel immunization strategies including vaccines that produce a robust immune response in older people.

Survival, differentiation and trafficking of T cells, and their role in protective immunity against pathogens
The Jameson lab is mainly focused on CD8 T cell responses against pathogens, but we also study CD4 T cells and B cells. Recent work involves surprising findings on the subsets of memory CD8 T cells that offer optimal protective immunity (i.e. the cells best suited to eliminate viral, bacterial and protozoan infections) – and the vaccination approaches that produce and sustain them. We also study a critical transcription factor called KLF2, which we showed regulates T and B cell differentiation, and has a central role in controlling recirculation of T cells. While some memory T cells recirculate, some stay in peripheral tissues (e.g. the skin, gut epithelium, etc.) and are called resident memory cells (TRM). In recent work we showed that KLF2 expression is lost in TRM, and that this step is critical for generating the TRM pool. Lastly, we investigate the mechanisms by which homeostatic mechanisms can drive naïve CD8 T cells to acquire memory T cell characteristics, and the significance of such cells in host defense. 

1) Protective immunity by CD8 T cells
CD8 T cells are capable of controlling many bacterial, viral and parasitic infections. Immune responses typically produce short-lived effector cells (most of which die around the time that the antigen/pathogen are cleared) and long-lived memory cells (which can support life-long immunity to reinfection). But the memory population contains several “types” or subsets of cells – which are most important for pathogen control? We investigated the function of a subset of memory CD8 T cells that keep expressing effector phenotype (“long-lived effector” cells), and were thought to be senescent cells with minimal capacity to respond. Unexpectedly, these long-lived effector cells offered optimal protective immunity against bacterial (Listeria monocytogenes) and viral (vaccinia) infections. We also studied vaccination approaches that efficiently generate the long-lived effector population. (For further details, look at Olson et al. 2013). We are exploring the basis for the improved protection by these cells, and extending the work on protective immunity to other infectious models (including malarial parasites). 

2) Function of Kruppel-like factors in T and B cells
Some years ago we discovered that the zinc-finger transcription factor KLF2 plays a key role in T cell migration, through regulation of numerous trafficking molecules involved in lymphoid tissue entry and egress (Carlson et al. 2006), and we subsequently found that KLF2 regulates T and B cell differentiation (Hart et al. 2011; Weinreich et al 2009; Interestingly, KLF2 expression is heterogeneous among memory T cells: KLF2 is highly expressed by memory CD8 T cells in lymphoid tissues and blood. However, KLF2 expression is extinguished in TRM in non-lymphoid tissues (as diverse as the small intestine, salivary gland, skin and brain), which are critical for effective control of infections at barrier surfaces. Our studies suggest that induced downregulation of KLF2 and its targets (especially the protein S1PR1) is essential for establishment of resident memory cells. Hence KLF2 acts as a switch to determine whether memory CD8 T cells are part of the recirculating or resident populations (Skon et al. 2013). We are following this work with new studies on a subset of CD4 T cells that become resident within lymphoid tissues. We’re also now exploring related KLFs for their role in the immune system. 

3) Homeostatic mechanisms regulating naïve T cell responses 
Memory T cells are not only produced during the response to foreign antigens: Our work defined at least two distinct pathways in which naïve CD8 T cells acquire memory-like properties, through the response to cytokines (including IL-7, IL-15 and IL-4) and interaction with self peptide/MHC molecules. Such memory populations exist in normal unimmunized mice, and these cells show functional properties (including pathogen protection) similar to “true” memory cells. We are investigating the role of these populations in normal immunity, and ways to harness “homeostatic memory” cells for improved protection against infection (see Lee et al. 2013, Akue et al.2012; Hamilton et al. 2010). Since lymphopenia can induce generation of homeostatic memory cells, these findings have relevance for immune function in immunocompromized individuals, including cancer patients undergoing radio- or chemo-therapy. Furthermore, we have found that heterogeneity among naïve CD8 T cells dictates both how they will respond to homeostatic cues, and how they will respond to foreign antigen stimulation. We are investigating the basis by which some naïve CD8 T cells are much more potent than others in their response to infection, and determining how this influences immune competence. 

Publications

  • Burrack KS, Huggins MA, Taras E, Dougherty P, Henzler CM, Yang R, Alter S, Jeng EK, Wong HC, Felices M, Cichocki F, Miller JS, Hart GT, Johnson AJ, Jameson SC, Hamilton SE.  Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells J Immuni.2018.03.012
  • Lee YJ, Starrett GJ, Lee ST, Yang R, Henzler CM, Jameson SC, Hogquist KA. Lineage-Specific Effector Signatures of Invariant NKT Cells Are Shared amongst ?? T, Innate Lymphoid, and Th Cells. J Immunol. 2016 Aug 15;197(4):1460-70. doi: 10.4049/jimmunol.1600643. Epub 2016 Jul 6.
  • Lee YJ, Wang H, Starrett GJ, Phuong V, Jameson SC, Hogquist KA. Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response. Immunity. 2015 Sep 15;43(3):566-78.
  • Xing Y, Wang X, Jameson SC, Hogquist KA. Late stages of T cell maturation in the thymus involve NF-?B and tonic type I interferon signaling. Nat Immunol. 2016 May;17(5):565-73. doi: 10.1038/ni.3419. Epub 2016 Apr 4.
  • Fraser, K.A., Rosato, P.C., Filali-Mouhim, A., Sekaly, R.P., Jenkins, M.K., Vezys, V., Haining, W.N., Jameson, S.C., and D. Masopust. (2016). Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532:512-516
  • Fulton, R.B.,Y. Xing, J.A. Best, A.W. Goldrath, K.A. Hogquist and S.C. Jameson. (2014) TCR sensitivity to self-peptide-MHC dictates naïve CD8 T-cells’ capacity to respond to foreign antigens. Nat.Imm. 16:107-117
  • Lee, J.-Y., C.N. Skon, Y.J. Lee, S. Oh, J.J. Taylor, D. Malhotra, M.K. Jenkins, M.G. Rosenfeld, K.A. Hogquist and S.C. Jameson. (2014) The transcription factor KLF2 restrains CD4+ T follicular helper cell differentiation. Immunity 42:252-264
  • Jameson SC, and Renkema, KR. (2014) An Uncommon Tail about the Common ?-Chain. Immunity 40 (6):  859–860
  • Skon, C.N., J.Y. Lee, K.G. Anderson, D. Masopust, K.A. Hogquist, and S.C. Jameson. (2013) Transcriptional downregulation of S1PR1 is required for establishment of resident memory CD8+ T-cells. Nature Immunology. 14:1285-1293
  • Lee YJ, Holzapfel KL, Zhu J, Jameson SC, and KA Hogquist. (2013) Steady state production of IL-4 modulates immunity in different strains and is determined by lineage diversity of iNKT cells. Nature Immunology 14:114.
  • Lee, J.Y., S.E. Hamilton, A.D. Akue, K.A. Hogquist and S.C. Jameson (2013). Virtual memory CD8 T cells display unique functional properties. PNAS 110:13498-13503.
  • Olson, J.A., C. McDonald-Hyman, S.C. Jameson* and S.E. Hamilton*. (2013) Effector-like CD8 T cells in the memory population mediate potent protective immunity. Immunity: 38:1250-1260. (*Co-corresponding authors.)
  • Johnson, L.D. and S.C. Jameson. (2012). TGF-b sensitivity restrains CD8+ T cell homeostatic proliferation by enforcing sensitivity to IL-7 and IL-15. PLoS One 7:e42268.
  • Hart, G.T. S.L. Peery, S.E. Hamilton and S.C. Jameson (2012). Cutting edge: Kruppel-like factor 2 is required for phenotypic maintenance but not development of B1 B cells. J.Immunol. 189:3293-3297.
  • Akue, A.D., J.-Y. Lee and S.C. Jameson. (2012) Derivation and maintenance of virtual memory CD8 T cells. J.Immunol. 188:2516-2523
  • Gomez-Olvera, I, S.E. Hamilton, Z. Xiao, C.P. Guimaraes, H. Ploegh, K.A. Hogquist and S.C. Jameson. (2012) Cholera toxin activates non-conventional adjuvant pathways that induce protective CD8 T cell responses after epicutaneous vaccination. Proc. Natl. Acad. Sci. (USA). 109:2072-2077.
  • Hart, G.T., X. Wang, K.A. Hogquist and S.C. Jameson. (2011) Kruppel-like factor 2 (KLF2) regulates B-cell reactivity, subset differentiation and trafficking molecule expression. Proc. Natl. Acad. Sci. (USA). 108:716-721.
  • Takada, K., X. Wang, G.T. Hart, O.A. Odumade, M.A. Weinreich, K.A. Hogquist and S.C. Jameson. (2011) KLF2 is required for trafficking but not quiescence in post-activated T cells. J.Immunol. 186:775-783.
  • Johnson, L.D. and S.C. Jameson (2010) Self-specific CD8+ T cells maintain a semi-naïve state following lymphopenia-induced proliferation. J.Immunol. 184:5604-5611
  • Sandau, M. M., J. E. Kohlmeier, D. L. Woodland and S. C. Jameson. (2010) IL-15 regulates both quantitative and qualitative features of the memory CD8 T cell pool. J.Immunol. 184:35-44.
  • Takada, K. and S.C. Jameson (2009) Naïve T cell homeostasis: From awareness of space to a sense of place. Nat. Rev. Imm. 9:823-832
  • Masopust, D. and S.C. Jameson (2009) Memory T cell diversity: An embarrassment of riches. Immunity 31:859-871
  • Takada, K. and S.C. Jameson. (2009) Self Class I MHC molecules support survival of naïve CD8+ T cells but depress their functional sensitivity through regulation of CD8 expression levels.J.Exp.Med. 206:2253-2269
  • Weinreich, M.A., K. Takada, C. Skon, S.L. Reiner, S.C. Jameson*, and K.A. Hogquist* (2009) KLF2 deficiency in T cells results in unrestrained cytokine production and bystander chemokine receptor upregulation. Immunity 31:122-130. (*Co-corresponding authors).
  • Haluszczak, C., A.D. Akue, S.E. Hamilton, L.D.S. Johnson, L.Pujanauski, L. Teodorovic, S.C. Jameson* and R.M. Kedl* (2009) The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion. J.Exp.Med. 206:435-448. (^Co-first authors; *Co-corresponding authors)
  • Sandau M.M., C.J. Winstead and S.C. Jameson. (2007) IL-15 is required for sustained lymphopenia-driven proliferation and accumulation of CD8 T cells. J. Immunol. 179:120-125
  • Carlson^ C.M., Endrizzi^ B.T., Wu J., Ding X., Weinreich M.A., Walsh E.R., Wani M.A., Lingrel J.B., Hogquist K.A., Jameson S.C. (2006). Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature. 442:299-302. (^Co-first authors. C.M. Carlson is a former MICaB student).
  • Hamilton S.E., M.C. Wolkers, S.P. Schoenberger and S.C. Jameson (2006). The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol. 7:475-481