Stephen Jameson, PhD

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

Stephen Jameson

Contact Info

[email protected]

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


The Jameson lab primarily focuses on the homeostasis, trafficking, and differentiation of CD8+ T cells, and how these can be regulated to promote beneficial responses and limit immunopathology.

Summary

Dr. Jameson studies the regulation of CD8 T cell development, homeostasis, and function. A major focus has been the factors, including cytokines, that induce and maintain protective memory CD8 T cells, capable of efficient control of pathogens and tumors. A related interest is on Tcell trafficking, including the cues that determine whether memory T cells patrol around the body (recirculating) or remain in tissues (resident). In particular, we explore the regulation of T cell trafficking by KLF2 and related transcription factors, testing how manipulation of T cell migration can be used to tailor T cell function. Other studies investigate the role of the innate immune “danger” signal receptor P2RX7, which we showed is also critical for supporting survival and metabolic fitness of long-lived memory CD8+ T cells; analysis of non-deletional mechanisms of immunological tolerance as a means to avoid autoimmunity; and work on the immune response to pathogens and allergens in mice with normal microbial experience (also called ‘dirty’ mice), which we showed are a more faithful model of the adult human immune system.

Expertise

Sophisticated mouse models of adaptive immunity; flow cytometry; NGS analysis (single-cell RNAseq, TCR repertoire analysis, etc.); mitochondrial and other metabolism assays; mouse models entailing physiological microbial exposure (“dirty” mice).

Awards & Recognition

  • Elected to the Council of the American Association of Immunologists, 2019-2026 
  • Appointed to the NCI Board of Scientific Counselors (Basic Sciences),2016-present
  • Elected into the 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.

The Jameson lab primarily focuses on the mechanisms that control development, homeostasis, and trafficking of naive and memory CD8+ T cells. As well as the regulation of protective immunity versus immunopathology in T cell responses. 

  • Physiological role of self-recognition by the T cell receptor: Recognition of “self” peptide/MHC molecules by the T cell receptor (TCR) is usually considered from the perspective of autoimmunity – but every T cell has to recognize self-ligands (in low affinity interactions) in order to mature in the thymus. We’ve investigated how these kinds of TCR interactions promote mature T cell survival and can even drive differentiation into a memory-like population (in conjunction with cytokine receptor stimulation). Furthermore, we discovered that the “strength” of the TCR encounter with self-peptide/MHC dictates a T cell’s reactivity to foreign antigens: naïve CD8+ T cells with features of greater “self-awareness” showed stronger responses to pathogens. This implies a degree of self-reactivity is beneficial for normal immune function. We’re also investigating how CD8+ T cell tolerance to self-peptide/MHC molecules is controlled. In a model we’ve investigated, involving tolerance to a melanocyte antigen, few self-specific T cells are eliminated during thymic development, and these cells are capable of a robust response to the self-antigen following immunization – however, these cells are poor at inducing immunopathology, suggesting tolerance is narrowly tailored to prevent overt tissue damage. We continue to explore how interactions with self- peptide/MHC ligands are critical to support T cell development, homeostasis and functional reactivity – and to understand how such interactions become unregulated, leading to autoimmunity.
  • Role and regulation of the CD8 coreceptor: The CD8 co-receptor is critical for coordinated binding of the TCR to Class I MHC molecules. We’ve shown that the strength of the CD8-Class I MHC interaction changes during T cell development, such that optimal interactions occur in developing thymocytes that also show a heightened TCR sensitivity for self-peptide/MHC, which is required for their maturation. We found that this developmental regulation of CD8-Class I MHC binding is regulated, at least in part, by changes in cell surface glycosylation as T cell mature. We also showed that CD8 expression itself is dynamically regulated following T cell activation, so that stimulated CD8+ T cells are temporarily “detuned” after activation, resulting in altered states of ligand recognition. Together, these findings suggest ways in which we might improve desirable CD8+ T cell responses (such as tumor immunotherapy) by enhancing CD8 binding to Class I MHC ligands.
  • CD8+T cell memory:A primary focus of the Jameson lab is CD8+ T cell memory, in all its varied forms. While memory cells are typically considered to arise following an immune response to foreign antigens, we discovered that homeostatic processes, involving TCR interactions with normal self-peptide/MHC ligands and exposure to homeostatic cytokines such as IL-7 and IL-15, lead “naïve” CD8+ T cells to acquire functional characteristics of “true” memory cells. We and others showed that such “virtual” memory cells arise physiologically in normal mice (and resemble a population in humans) and that these cells participate in the response to pathogens, exhibiting a distinct differentiation program from naïve cells. How these cells contribute to immune readiness toward new infections is an active area of interest.
       We also study conventional memory cells, with a special focus on how distinct “subsets” of memory cells offer distinct mechanisms of protective immunity. For example, some memory CD8+ T cells are embedded in tissues and do not enter the circulation during normal homeostasis (“resident memory” T cells, TRM), while others appear to primarily patrol the blood vasculature, without routinely entering tissues. We are especially interested in what regulates the decision of memory precursors to become distinct memory cell subsets. We recently showed that a purinergic receptor called P2RX7 is critical for generation of CD8+ TRM and “central” memory cells but is largely dispensable for other memory subsets. This was intriguing because the best studied role of P2RX7 is as a receptor for “danger” signals, as a way of activating the innate immune cells to current tissue damage – our data show that P2RX7 has quite distinct role in supporting the metabolic fitness of long-term memory CD8+ T cells. We’re currently exploring how P2RX7 and related molecules control CD8+ T cell tumor immunotherapy. Other studies have focused on molecules that are associated with resident versus recirculating cells - distinguishing proteins that are valuable markers but play a limited functional role (such as CD69) from others that have actual functional significance (such as ICOS and S1PR1).
  • Control of lymphocyte trafficking and differentiation by KLF2: We began working on the transcription factor Kruppel-like factor 2 (KLF2, also called LKLF) because it was thought to be a key player in regulating naïve T cell quiescence. Instead, we found that a primary role of KLF2 is to regulate T cell trafficking – two prominent targets of KLF2 being CD62L (L-selectin) and S1PR1 (a receptor for sphingosine-1-phosphate, essential for lymphocyte egress into blood and lymph). This led to an entirely new understanding of both the function of KLF2 and, more broadly, the mechanisms that control thymocyte egress to the periphery and T cell recirculation. We went on to show that decreased expression of KLF2 (and its target S1PR1) is critical for generating CD8+ TRM in non-lymphoid tissues, but also is critical for generating differentiation of CD4T cells into “follicular helper” T cells TFH in the germinal center of lymphoid tissues. These and other intriguing parallels indicate similar regulation modules are at play in controlling localization versus dissemination of T cells (and possibly other lymphocytes) through regulation of KLF2 and other KLF transcription factors. 
  • Evaluation of mice with normalized immunological experience: In a long-term collaboration with the Masopust and Hamilton-Hart labs, we’ve studied how a more physiological exposure to natural mouse pathogens and commensal microbes impacts the immune system in laboratory mice – and the validity of mice as a model for the adult human immune system. To do so we examined mice that were not maintained under typical Specific Pathogen Free (SPF) housing conditions but were exposed to natural microbe transmission from mice purchased from a pet store. This results in widespread immune activation in the inbred mice and substantial and sustained changes in numerous immunological parameters. We showed that these so-called “dirty mice” had characteristics that a more faithful reflection of the immune system in adult humans (while conventional SPF mice more accurately reflect the immune system in neonatal humans). We’ve investigated how microbial experience influences the response to novel infections, immunopathology and the response to allergens, among other immune parameters. These studies show widespread changes in the nature of many (but not all) immune responses, suggesting exposure to microbes causes permanent remodeling of the immune system, producing a “new normal” baseline of immune readiness. 

Publications


For a full list of publications: Link here


Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells.  Georgiev, H., Peng, C., Huggins, M.A., Jameson S. C., Hogquist, K.A.  Nat Commun 12, 2308 (2021). https://doi.org/10.1038/s41467-021-22589-z

T Cell Memory: Understanding COVID-19.
Jarjour NN, Masopust D, Jameson SC. Immunity. 2021 Jan 12;54(1):14-18. doi: 10.1016/j.immuni.2020.12.009. Epub 2020 Dec 19. PMID: 33406391

The Naming of Memory T-Cell Subsets.
Jameson SC.Cold Spring Harb Perspect Biol. 2021 Jan 4;13(1):a037788. doi: 10.1101/cshperspect.a037788. PMID: 33229439

The relationship between CD4+ follicular helper T cells and CD8+ resident memory T cells: sisters or distant cousins?
Peng C, Jameson SC.Int Immunol. 2020 Sep 8;32(9):583-587. doi: 10.1093/intimm/dxaa045. PMID: 32620009

Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8+ Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-b. Borges da Silva H, Peng C, Wang H, Wanhainen KM, Lopez S, Khoruts A, Zhang N, Jameson SC. Immunity.2020 Jul 14:53(1):158-171.e6.doi:10.1016/j.immuni.2020.06.010. PMID: 32640257

New Insights into the Immune System Using Dirty Mice. Hamilton SE, Badovinac VP, Beura LK, Pierson M, Jameson SC, Masopust D, Griffith TS. J Immunol. 2020 Jul 1;205(1):3-11. doi: 10.4049/jimmunol.2000171. PMID: 32571979

The Functional Requirement for CD69 in Establishment of Resident Memory CD8+ T Cells Varies with Tissue Location. Walsh DA, Borges da Silva H, Beura LK, Peng C, Hamilton SE, Masopust D, Jameson SC. J Immunol. 2019 Aug 15;203(4):946-955. doi: 10.4049/jimmunol.1900052. Epub 2019 Jun 26. PMID: 31243092

Self-Regulation of Memory CD8 T Cell Metabolism through Extracellular ATP Signaling. Wanhainen KM, Jameson SC, da Silva HB. Immunometabolism. 2019;1(1):e190009. doi: 10.20900/immunometab20190009. Epub 2019 Jul 23. PMID: 31428464

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets. Borges da Silva H, Wang H, Qian LJ, Hogquist KA, Jameson SC. J Immunol. 2019 Apr 1;202(7):2153-2163. doi: 10.4049/jimmunol.1801613. Epub 2019 Feb 18. PMID: 30777922

The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Borges da Silva H, Beura LK, Wang H, Hanse EA, Gore R, Scott MC, Walsh DA, Block KE, Fonseca R, Yan Y, Hippen KL, Blazar BR, Masopust D, Kelekar A, Vulchanova L, Hogquist KA, Jameson SC. Nature. 2018 Jul;559(7713):264-268. doi: 10.1038/s41586-018-0282-0. Epub 2018 Jul 4. PMID: 29973721

Understanding Subset Diversity in T Cell Memory. Jameson SC, Masopust D. Immunity. 2018 Feb 20;48(2):214-226. doi: 10.1016/j.immuni.2018.02.010. PMID: 29466754

Of Mice, Dirty Mice, and Men: Using Mice To Understand Human Immunology. Masopust D, Sivula CP Jameson SC. J Immunol. 2017 Jul 15;199(2):383-388. doi: 10.4049/jimmunol.1700453. PMID: 28696328

IL-4 sensitivity shapes the peripheral CD8+ T cell pool and response to infection. Renkema KR, Lee JY, Lee YJ, Hamilton SE, Hogquist KA, Jameson SC. J Exp Med. 2016 Jun 27;213(7):1319-29. doi: 10.1084/jem.20151359. Epub 2016 Jun 13. PMID: 27298446

Normalizing the environment recapitulates adult human immune traits in laboratory mice. Beura LK, Hamilton SE, Bi K, Schenkel JM, Odumade OA, Casey KA, Thompson EA, Fraser KA, Rosato PC, Filali-Mouhim A, Sekaly RP, Jenkins MK, Vezys V, Haining WN, Jameson SC, Masopust D. Nature. 2016 Apr 28;532(7600):512-6. doi: 10.1038/nature17655. Epub 2016 Apr 20. PMID: 27096360

The transcription factor KLF2 restrains CD4+ T follicular helper cell differentiation. Lee JY, Skon CN, Lee YJ, Oh S, Taylor JJ, Malhotra D, Jenkins MK, Rosenfeld MG, Hogquist KA, Jameson SC. Immunity. 2015 Feb 17;42(2):252-264. doi: 10.1016/j.immuni.2015.01.013. PMID: 25692701

Innate memory T cells. Jameson SC, Lee YJ, Hogquist KA. Adv Immunol. 2015;126:173-213. doi: 10.1016/bs.ai.2014.12.001. Epub 2015 Feb 7. PMID: 25727290

The TCR's sensitivity to self peptide-MHC dictates the ability of naive CD8+ T cells to respond to foreign antigens. Fulton RB, Hamilton SE, Xing Y, Best JA, Goldrath AW, Hogquist KA, Jameson SC. Nat Immunol. 2015 Jan;16(1):107-17. doi: 10.1038/ni.3043. Epub 2014 Nov 24. PMID: 25419629

Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Skon CN, Lee JY, Anderson KG, Masopust D, Hogquist KA, Jameson SC. Nat Immunol. 2013 Dec;14(12):1285-93. doi: 10.1038/ni.2745. Epub 2013 Oct 27. PMID: 24162775

Virtual memory CD8 T cells display unique functional properties. Lee JY, Hamilton SE, Akue AD, Hogquist KA, Jameson SC. Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13498-503. doi: 10.1073/pnas.1307572110. Epub 2013 Jul 29. PMID: 23898211

Effector-like CD8+ T cells in the memory population mediate potent protective immunity. Olson JA, McDonald-Hyman C, Jameson SC, Hamilton SE. Immunity. 2013 Jun 27;38(6):1250-60. doi: 10.1016/j.immuni.2013.05.009. Epub 2013 Jun 6. PMID: 23746652

Cholera toxin activates non-conventional adjuvant pathways that induce protective CD8 T cell responses after epicutaneous vaccination. Gomez-Olvera, I, S.E. Hamilton, Z. Xiao, C.P. Guimaraes, H. Ploegh, K.A. Hogquist and S.C. Jameson. (2012). Proc. Natl. Acad. Sci. (USA). 109:2072-2077. PMID: 22308317

Krüppel-like factor 2 (KLF2) regulates B-cell reactivity, subset differentiation, and trafficking molecule expression. Hart GT, Wang X, Hogquist KA, Jameson SC. Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):716-21. doi: 10.1073/pnas.1013168108. Epub 2010 Dec 27. PMID: 21187410