Education

• 1987 - B.A. University of La Verne, La Verne, CA

Thesis: Mutagenic Potential of Common Chemicals using the Yeast Rho mutation as a readout.  Mentors:  Wendy Wooten and David Flittner

• 1992 - M.S. Emphasis in Microbiology and Immunology, California State Polytechnic University, Pomona, CA.

Thesis: Studies of the phagocytic capabilities of cultured epidermal Langerhans Cells and subsequent fungicidal activity after incubation with free and liposome encapsulated Amphotericin B.  Mentors:  Pamela Sperry and Jill Adler-Moore

• 2001 - Ph.D. in Immunology, Oregon Health Sciences University, Portland, OR.

Thesis: Imaging and analysis of the Immunological Synapse Formed Between CD4⁺ T lymphocytes and Antigen Presenting Cells.  Mentor:  David C. Parker

Courses Taught

BIOB 410 - Immunology

BIOB 411 - Immunology Lab

MICB 502 - Advanced Immunology

BIOB 596 - Principles of Light Microscopy

Teaching Experience

1996 - 2004        Instructor, Medical School Immunology, Oregon Health & Science University

1997 - 2004        Instructor, Clinical Laboratory Science Program, Oregon Health & Science University

2002 – 2004       Instructor, Biotechnology Department, Portland Community College

2002 – 2011        Faculty Member, International Course on 3D Microscopy of Living Cells, University of British Columbia, Vancouver, BC, Canada

2005 - 2013        Assistant Professor, Division of Biological Sciences and Center for Environmental Health Sciences, University of Montana, Missoula, MT

2013 - Present    Associate Professor, Division of Biological Sciences and Center for Environmental Health Sciences, University of Montana, Missoula, MT

Research Interests

Work in my lab focuses on CD4⁺ T lymphocyte activation and subset differentiation.

We have 2 basic Research Areas:

     1. The biological consequences for individual T cells of signaling induced by APC-derived membrane molecules after their transfer to T cells at the T-APC immunological synapse, a process termed “trogocytosis”.

     2. The impact of the herbicide Atrazine on the activation of CD4⁺ T cells and the mechanism underlying a significant increase in Foxp3⁺ regulatory T cells

The Role of Trogocytosis-Mediated Signaling in CD4 Effector Subset and Memory T Cell Differentiation

CD4⁺ T lymphocytes recognize antigenic peptide fragments presented on the surface of antigen presenting cells (APC) by major histocompatibility complex (MHC) class II proteins. This initial antigen recognition is followed by large-scale spatial and temporal molecular rearrangements of plasma membrane proteins and intracellular signaling molecule leading to the formation of an ordered structure at the T-APC interface termed the immunological synapse. The synapse is involved in T cell signaling as well as the site for delivery of T cell effector functions. Our lab has previously shown that that molecules from the APC are transferred to the T cell at the immune synapse in a process called trogocytosis. This process is seen below with GFP-tagged MHC:peptide on the antigen presenting cell (green) and T cells (shown in polarized light in blue). 

We are examining the biological significance of intercellular transfer of molecules from APC to T cells. We've shown that APC-derived molecules continue to engage their receptors on T cell and sustain intracellular signaling within the T cell, as shown in the movie below with co-localization of trogocytosed MHC:peptide (green), total phosphorylated tyrosine (blue) and phosphoylated Lck (red).  

This signaling leads to the selective survival of these T cells in culture and drives the production of some effector cytokines (e.g. IL-4, IL-6, IL-21), while inhibiting production of other cytokines (e.g. IFN-gamma). Our work has shown that trogocytosis-mediated signaling ultimately induces expression of transcription factors and effector cytokines within the cells consistent with differentiation of cells towards a T_H2 phenotype. The trogocytosis-mediated signaling also can induce the conversion of polarized T_H1 cells toward a T_H2 phenotype.  We hypothesize that this may play an important role in control of immune responses - promoting T_H2 and limiting potentially damaging T_H1 responses.

In addition to driving T_H2-associated gene expression patterns, we have also observed that trogocytosis-mediated signaling induces a cellular phenotype consistent with a second CD4 effector subset, the Bcl-6⁺IL-21⁺CXCR5⁺ follicular T helper cells (T_FH).  Our current work involves examining the potential for trogocytosis-mediated signaling to controbute to CD4 differentiation into T_FH cells and analyze its impact on antibody responses in vivo.  

Finally, we are just beginning experiments to analyze whether trogocytosis and trogocytosis-mediated signaling have a role in asymmetrical division and the development of CD4⁺ memory T cells from naive precursors.  

Immunotoxicology of Atrazine

We are examining the impact on Atrazine on the activation and differentiation of CD4⁺ T cells.  Atrazine is a very widely applied herbicide that the USGS  estimates contaminates 70% of the ground water in the US. It has been linked to birth defects, cancer, immune developmental defects and  modulation of immune cell effector functions. We have shown that Atrazine inhibits CD4⁺ T lymphocyte proliferation and effector function.  In addition, we have shown that the frequency of Foxp3 positive regulatory T cells (Treg) doubles in atrazine-treated cultures. This is largely due to elevated levels of cAMP, as Atrazine is a potent phosphodiesterase inhibitor.  We have recently found that male and female T cells respond differently to atrazine exposure.  Atrazine's other biochemical effect is to induce expression of aromatase, which converts androgens to estrogen. We are currently examining the impact of Atrazine-induced elevated estrogen on the induction of Tregs and Atrazine-associated inhibition of T cell activation.

We are also examining whether the effects of atrazine on T cell function and fate are directly on the T cell or whether it is working via altering antigen presenting cell phenotype/activity.  

Our ultimate goal with this project is to examine whether atrazine exposure alters or limits an in vivo immune response to tumors or infectious disease.  

Field of Study

Cellular Immunology

CD4⁺ T Cell Subset Differentiation

Trogocytosis-Mediated Signaling

Immunotoxicology

Selected Publications

Reed, S.J., Reichelt, M., and Wetzel, S.A. (2021). Lymphocytes and Trogocytosis-Mediated Signaling, Cells10(6):1478 PMC8231098

Reed, S.J. and Wetzel, S.A.  (2019) Trogocytosis-Mediated Intracellular Signaling in CD4⁺ T Cells Drives T_H2-Associated Effector Cytokine Production and Differentiation.  The Journal of Immunology.  202 (10): 2873-2887. PMCID: PMC6504583

Osborne, D.G. and Wetzel, S.A. (2012) Trogocytosis leads to sustained signaling in CD4⁺ T cells. The Journal of Immunology, 189(10):4728-39.  PMID: 23066151

Scott A. Wetzel, T. W. McKeithan, D.C. Parker. (2005). Peptide-specific intercellular transfer of MHC class II to CD4⁺ T cells directly from the immunological synapse upon cellular dissociation. The Journal of Immunology. 174(1): 80-9

Publications

Affiliations

American Association of Immunologists

University of Montana Center for Environmental Health Sciences (CEHS)

UM Interdepartmental Immunology Graduate Degree Track

UM DBS Cellular, Molecular, Microbial Biology (CMMB) Graduate Program

UM Molecular Bioscience Gratuate Program (MBS)

UM Toxicology Graduate Program

Professional Experience

1991 - 1994       Research Associate II, Division of Immunology, City of Hope National Medical Center, Duarte, CA. 

1994 - 2001       Ph.D. Student. Molecular Microbiology and Immunology Department, Oregon Health Sciences University, Portland, OR.

2002 - 2005       Post-Doctoral Fellow, Molecular Micribiology and Immunoloty Department, Oregon Health Sciences University, Portland, OR