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MICaB Faculty

Stephen Jameson
Stephen C. Jameson, Ph.D.

Professor

Department of Laboratory Medicine and Pathology

Cambridge, 1988, Ph.D.

612-625-1496 - office
612-625-1626 - lab
Lab website http://www.jamequist.umn.edu/

E-mail:james024@umn.edu


Research Interests:

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. 

Selected Recent Publications (MICaB students highlighted in red):

  • 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.  In Press: Nature Immunology
  • 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