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DepartmentMicrobiology, Immunology & Molecular Genetics
Leadbetter, Elizabeth A., Ph.D.
Dr. Leadbetter’s laboratory has two long term research goals, to thoroughly investigate the mechanisms and nature of cooperation between iNK T and B cells during responses to model and bacterial lipid antigens and to extend these finding to inform the development of a new family of lipid based vaccine candidates. Her studies focus on the fascinating interplay between innate and adaptive immune responses. Dr. Leadbetter’s initial studies in immunology were the first to describe the activation of autoreactive B cells by immune complexes containing antibodies and self-DNA, through the co-ligation of the B cells receptor and Toll-like receptor 9 (TLR9). She later established a research program that applied this same concept to a new innate player, the lipid-antigen-secific invariant NK T (iNKT) cell. These studies currently include studies of model lipid, protein, and polysaccharide antigens in murine models of infection, metabolic disease, and autoimmunity; including clinically relevant vaccine studies harnessing iNKT and B cell cooperation for protection.
PhD, Microbiology and Immunology at Boston University School of Medicine, Boston, MA
Postdoctoral Fellowship, Brigham & Women’s Hospital/Harvard Medical School, Boston, MA
The Leadbetter laboratory has two long term research goals: to investigate the mechanisms and nature of cooperation between iNKT and B cells during acute responses (infection) and chronic inflammation (autoimmunity and obesity) and to translate this knowledge into a new family of lipid-based vaccine candidates and/or autoimmune interventions.
Leukocyte interplay during the chronic inflammation of obesity
Obesity is linked to chronic, low-grade inflammation in visceral adipose tissue and an associated spectrum of metabolic abnormalities including insulin resistance and T2D. We previously discovered that neutrophils license iNKT cells to regulate autoreactive B cells during IL-18-mediated chronic inflammation in the spleen, but crosstalk between these cell subsets remains unexplored in the setting of obesity and T2D.
The Leadbetter lab was the first in the world to develop an innovative confocal imaging technique to identify iNKT cells in situ using fresh tissue sections. We now integrate this approach with sophisticated in vivo murine models including high fat diet-induced obesity, cytokine reporter mouse strains, and mixed bone marrow chimeras to study adipose leukocytes. We complement our murine studies with 13+ color flow cytometry of ex vivo and in vitro cultured human lymphocytes isolated from the adipose tissue of lean and obese patients. This project is dissecting the interplay of iNKT cells, neutrophils, and B cells in the context of both murine and human obesity to understand the immunological implications of this public health epidemic and contribute to high priority national and international efforts to stem the tide of obesity. Our objective is to define new immunotherapeutic targets to reverse the development of T2D in obesity.
Our location in San Antonio has uniquely positioned us to succeed in performing these studies. San Antonio was recently identified as having the second highest level of obesity of any major city in the U.S. (>31%) so clinical samples and clinical practicioners with relevant obesity and T2D expertise are readily accessible. Dr. Michael Decherd (San Antonio Plastic Surgery Institute), Dr. Robert Schenken (Obstetrics and Gynecology; UTHSCSA), and Dr. Richard Peterson (Bariatric and Metabolic Surgery UT Medicine) provide subcutaneous and omental adipose tissue from patients undergoing elective surgeries in their practices. We routinely analyze fresh human adipose samples from both lean and obese patients.
Hagglof, T; Sedimbi, SK; Yates, JL; Parsa, R; Salas, BH; Harris, RA; Leadbetter, EA*; Karlsson, MCI*. Neutrophils license iNKT cells to regulate self-reactive mouse B cell responses. Nature Immunology 2016; advanced online publication Oct. 31, 2016. *contributed equally.
Lynch L; Michelet X; Zhang S; Brennan PJ; Moseman A; Lester C; Vomhof-Dekrey EE; Tighe M; Koay HF; Godfrey DI; Leadbetter EA; Sant’Angelo DB; von Andrian U; Brenner MB. Regulatory iNKT cells lack PLZF and control Treg and macrophage homeostasis in adipose tissue. Nature Immunology 2015 Jan;16(1):85-95. doi: 10.1038/ni.3047. Epub 2014 Dec 1.
King IL, Amiel E, Tighe M, Mohrs K, Veerapen N, Besra G, Mohrs M, Leadbetter EA. The mechanism of splenic invariant NKT cell activation dictates localization in vivo. J Immunol. 2013 Jul 15;191(2):572-82. Epub 2013 Jun 19.
Cooperation of NKT cells and B cells in response to lipid antigens
Different from protein-reactive T cells, iNKT cells are a unique cell population that recognizes lipids in the context of the CD1 family of antigen presenting molecules. Certain B cells recognize and internalize lipids and also express CD1 molecules on their surface, which makes them ideal partners for iNKT cells. Upon activation, iNKT cells express co-stimulatory molecules and release cytokines which helps CD1d-expressing B cells to proliferate and increase their secretion of antibodies. Thus, iNKT cells can improve a B cell’s response to antigens that they recognize in common.
Dr. Leadbetter’s lab has already demonstrated that this cooperation happens using a model lipid conjugate. However, B cells receiving cognate iNKT cell help have a profoundly different developmental outcome than B cells receiving non-cognate help involving both iNKT cells and protein-reactive CD4+ T cells. Cognate iNKT cell help drives a rapid, but un-sustained, GC B cell expansion but no B cell memory. Non-cognate iNKT cell help drives later GC B cell expansion more consistent with protein responses and induces a robust B cell memory response. We are using complex in vivo murine models, unique haptenated glycolipids, flow cytometry, and RNA array analysis to investigate the mechanisms of iNKT cell help which mediate this difference. Long term goals are to understand the interplay of iNKT and B cells and to harness this unique system to understand the global requirements for humoral B cell memory.
Vomhof-Dekrey EE; Yates J; Hägglöf T; Lanthier P; Amiel E; Veerapen N; Besra GS; Karlsson MCI; Leadbetter EA. Cognate interaction with iNKT cells activates B cells to produce IL-10. Proc Natl Acad Sci USA. 2015 Oct 6;112(40):12474-9. doi: 10.1073/pnas.1504790112. Epub 2015 Sep 21.
Vomhof-DeKrey EE; Yates J; Leadbetter EA. Invariant NKT cells provide innate and adaptive help for B cells. Curr Opin Immunol. 2014 Feb 7;28C:12-17. doi: 10.1016/j.coi.2014.01.007.
King IL, Fortier A, Tighe M, Dibble J, Watts G, Veerapen N, Haberman A, Besra GS, Mohrs M, Brenner MB, Leadbetter, EA. iNKT cells direct B cell responses to cognate lipid antigen in an interleukin 21-dependent manner. Nature Immunology 2011; Nov 27, 13(1): 44-50.
*Nature Immunology News & Views 2012; 13(1): 11-13.
*Nature Reviews Immunology 2012; 12(1):5.
Leadbetter EA, Brigl M, Illarionov P, Cohen N, Luteran M, Pillai S, Besra G, Brenner MB. NK T cells provide lipid antigen-specific cognate help for B cells. Proc Natl Acad Sci USA 2008; Jun 17, 105(24):8339-44. Epub 2008 Jun 11.
Glycolipid-based vaccine strategies for tumor immunotherapy
Current cancer immunotherapy strategies employ monoclonal antibodies, antitumor vaccines, and vaccine adjuvants in order to stimulate a patient’s own immune system to combat cancer. However, there is a critical need for additional therapeutic approaches as an effective, targeted immune response is crucial in order to eliminate a well-established, proliferating tumor. Invariant natural killer (iNK) T cells, a subset of T cells, are a potential immunotherapeutic target as they bridge cellular and humoral immunity by both directly killing tumor cells and facilitating protective immune responses of CD8+ T through direct and indirect killing. The most well studied glycolipid, alpha-galactosylceramide (αGalCer), is capable of rapidly activating iNKT cells to proliferate and secrete Th1 and Th2-type cytokines. αGalCer has also been utilized as a vaccine adjuvant to induce both humoral and cellular antitumor immune responses; however, high doses of αGalCer provide vigorous initial activation of iNKT cells, but subsequent injections result in anergy, or inactivation. To overcome this limitation, our lab has recently used biodegradable nanoparticles to deliver low doses of glycolipid adjuvant in combination with pathogen-derived antigens to successfully protect against lethal infection without inducing iNKT anergy. We hypothesize that this approach will be equally effective in driving responses to tumor antigens. Nanoparticles are safe, biodegradable polymers able to enhance the activity of encapsulated glycolipid adjuvants 1000-fold. Furthermore, nanoparticles can be embedded with pathogen-derived antigens to facilitate activation of relevant CD8+ T cell subpopulations. We are using nanoparticle delivery of low doses of glycolipid adjuvant in combination with tumor associated antigens (TAA) to circumvent iNKT anergy and induce protective IgG and CD8+ T cell responses against established tumors.
Glycolipid-based vaccine strategies for infectious disease protection
Most successful human vaccines elicit protective antibodies. CD4+ T cell help is essential for a strong humoral immune response, especially against poorly immunogenic polysaccharide antigens. To accomplish this, B cell antigens are typically conjugated to highly immunogenic T cell epitopes. iNKT cells are an innate glycolipid-specific lymphocyte subset of T cells restricted to the non-polymorphic antigen presenting molecule CD1d, which rapidly produce cytokines when activated. Because CD1d is non-polymorphic iNKT cells should respond to glycolipid stimulation equally well in everyone. Relatedly, we and others have recently shown that by activating iNKT cells, glycolipids can serve as robust adjuvants for co-administered protein and polysaccharide antigens. However, high doses of glycolipid tend to induce an anergic state in iNKT cells. To overcome this limitation, low doses of iNKT-activating glycolipids need to be administered in a highly efficient manner. Nanoparticle vaccines are a well-studied platform for delivering low doses of glycolipid adjuvant. Nanoparticles are safe, biodegradable polymers able to enhance the activity of encapsulated glycolipid adjuvants 1000-fold. Furthermore, nanoparticles can be embedded with B cell antigens to facilitate their targeting and uptake by relevant B cell subpopulations. We are currently testing nanoparticle delivery of low doses of glycolipid adjuvant with polysaccharide B cell antigen can circumvent anergy and induce protective IgG against systemic infection with an encapsulated pathogen, Streptococcus pnemoniae. This is a proof of principle study which will test a universal approach that could apply to most types of bacteria, fungi, parasites, or other pathogens.
Elizabeth Leadbetter graduated from Bates College in Lewiston, Maine in 1993, worked at Immulogic Pharmaceutical Corp, and then received her Ph.D. in 2002 from Boston University School of Medicine where she studied with Dr. Ann Marshak-Rothstein. She conducted her postdoctoral research at Brigham & Women’s Hospital; Harvard Medical School, Boston, MA in the lab of Dr. Michael Brenner. In 2009, she joined the faculty at the Trudeau Institute in Saranac Lake, NY as an Assistant Member. In 2015 she moved her laboratory to the University of Texas Health Science Center at San Antonio where she is currently an Associate Professor. She is a member of the American Association of Immunologists and currently serves as chair of the MIMG department Faculty Recruitment Committee.
Awards & Accomplishments
2000, 2001 Henry I. Russek Student Achievement Award 2nd place
2001 Lawrence M. Corwin Graduate Student Award
2002 Microbiology Department Graduate Student Travel Award
2002 Keystone Symposia Student Travel Award
2002 President’s Award, Boston University Science and Technology Day
2004-2007 Irvington Institute for Immunologic Research Postdoctoral Fellowship/Biogen-IDEC Foundation Fellow
2006 Keystone Symposia Travel Award
2013-2014 AAI Public Policy Fellow
2014 AAI Early Career Faculty Travel Award
Current Lab Members
Briana Hauff Salas
Leadbetter Lab Alumni
PhD research Scientist; Vertex Pharmaceuticals Corp., Montreal, CN
PhD Research Affiliate; Wadsworth Center, Albany, NY
PhD Assistant Professor; University of Vermont, Burlington, VT
PhD Research Assistant Professor; University of North Dakota, Grand Forks, ND
- Member, American Association of Immunologist (AAI)
Associated Core Facilities (http://iims.uthscsa.edu/ttr_core_facilities.html)
- UTHSCSA Flow Cytometry Core: (http://research.uthscsa.edu/facs/)
- UTHSCSA Optical Imaging Facility: (http://uthscsa.edu/csa/imaging.asp)
- Barshop Institute for Longevity and Aging Studies: (http://barshopinstitute.uthscsa.edu/main/core)
- UTHSCSA Bioanalytics and Single-Cell Core: (http://molecularmedicine.uthscsa.edu/research.aspx)
- UTHSCSA Mass Spectrometry/Lipidomics Core: (http://research.uthscsa.edu/mass-spectrometry/)
- UTHSCSA Genomics Resources Core: (http://uthscsa.edu/csa/genomics.asp)
Up to date listing of Leadbetter publications on PubMed:
- Hagglof, T; Sedimbi, SK; Yates, JL; Parsa, R; Salas, BH; Harris, RA; Leadbetter, EA*; Karlsson, MCI*. Neutrophils license iNKT cells to regulate self-reactive mouse B cell responses. Nature Immunology 2016; advanced online publication Oct. 31, 2016. *contributed equally.
- Vomhof-Dekrey EE; Yates J; Hägglöf T; Lanthier P; Amiel E; Veerapen N; Besra GS; Karlsson MCI; Leadbetter EA. Cognate interaction with iNKT cells activates B cells to produce IL-10. Proc Natl Acad Sci USA. 2015 Oct 6;112(40):12474-9. doi: 10.1073/pnas.1504790112. Epub 2015 Sep 21.
- Lynch L; Michelet X; Zhang S; Brennan PJ; Moseman A; Lester C; Vomhof-Dekrey EE; Tighe M; Koay HF; Godfrey DI; Leadbetter EA; Sant’Angelo DB; von Andrian U; Brenner MB. Regulatory iNKT cells lack PLZF and control Treg and macrophage homeostasis in adipose tissue. Nature Immunology 2015 Jan;16(1):85-95. doi: 10.1038/ni.3047. Epub 2014 Dec 1.
- Blackman MA; Yates JL; Spencer CM; Vomhof-Dekrey EE; Cooper AM; Leadbetter EA. The Yin and Yang of Inflammation. Curr Mol Med 2014. Oct 15 [Epub ahead of print].
- Siegmann N; Worbs D; Effinger F; Bormann T; Gebhardt M; Ulrich M; Wermeling F; Muller-Hermelink E; Biedermann T; Tighe M; Edwards MJ; Caldwell C; Leadbetter E; Karlsson MCI; Becker KA; Gulbins E; Doring G. Invariant natural killer T (iNKT) cells prevent autoimmunity, but induce pulmonary inflammation in cystic fibrosis. Cellular Physiology and Biochemistry2014; 34: 71-81. Doi:1159/000362985.
- Vomhof-DeKrey EE; Yates J; Leadbetter EA. Invariant NKT cells provide innate and adaptive help for B cells. Curr Opin Immunol. 2014 Feb 7;28C:12-17. doi: 10.1016/j.coi.2014.01.007.
- King IL, Amiel E, Tighe M, Mohrs K, Veerapen N, Besra G, Mohrs M, Leadbetter EA. The mechanism of splenic invariant NKT cell activation dictates localization in vivo. J Immunol. 2013 Jul 15;191(2):572-82. Epub 2013 Jun 19.
- Detre C, Keszei M, Garrido-Mesa N, Kis-Toth K, Castro W, Agyemang AF, Veerapen N, Besra GS, Carroll MC, Tsokos GC, Wang N, Leadbetter EA, Terhorst C. SAP expression in invariant NKT cells is required for cognate help to support B-cell responses. Blood. 2012 Jul 5;120(1):122-9. Epub 2012 May 21.
- King, IL… Fortier A, Tighe M, Dibble J, Watts G, Veerapen N, Haberman A, Besra GS, Mohrs M, Brenner MB, Leadbetter, EA. iNKT cells direct B cell responses to cognate lipid antigen in an interleukin 21-dependent manner.
Nature Immunology 2011; Nov 27, 13(1): 44-50.
*Nature Immunology News & Views 2012; 13(1): 11-13.
*Nature Reviews Immunology 2012; 12(1):5.
- Brigl, M, Tatituri, Raju VV, Watts, Gerald FM, Bhowruth V, Leadbetter EA, Barton N, Cohen NR, Hsu FF, Besra GS, Brenner MB. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med2011( 208):1163-1177.
- Veerapen N, Leadbetter EA, Brenner MB, Cox LR, Besra GS. Synthesis of a novel alpha-galactosyl ceramide haptenated-lipid antigen, a useful tool in demonstrating the involvement of iNKT cells in the production of antilipid antibodies. Bioconjug Chem 2010; Apr 21(4): 741-7.
- Leadbetter EA, Brigl M, Illarionov P, Cohen N, Luteran M, Pillai S, Besra G, Brenner MB. NK T cells provide lipid antigen-specific cognate help for B cells. Proc Natl Acad Sci USA 2008; Jun 17, 105(24):8339-44. Epub 2008 Jun 11.
- van den Elzen P, Garg S, Leon L, Brigl M, Leadbetter EA, Gumpertz JE, Dasher CC, Cheng TY, Sacks FM, Illarionov PA, Besra GS, Moody DB, Brenner MB. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 2005; Oct 6, 437 (7060): 906-10.
- William J, Euler C, Leadbetter E, Marshak-Rothstein A, Shlomchik MJ. Visualizing the onset and evolution of an autoantibody response in systemic autoimmunity. J Immunol 2005; June 1, 174(11): 6872-8.
- Rifkin IR, Leadbetter EA, Busconi L, Viglianti G, Marshak-Rothstein A. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev. 2005; Apr, 204: 27-42.
- Marshak-Rothstein A, Busconi L, Lau CM, Tabor AS, Leadbetter EA, Akira S, Krieg AM, Lipford GB, Viglianti GA, Rifkin IR. Comparison of CPG s-ODNs, chromatin immune complexes, and dsDNA fragment immune complexes in the TLR9-dependent activation of rheumatoid factor B cells. J Endotoxin Res. 2004; 10(4): 247-51.
- Leadbetter EA, Rifkin IR, Marshak-Rothstein A. Toll-like receptors and activation of autoreactive B cells. Curr Dir Autoimmunity 2003; 6:105-22.
- Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-Ig complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002; Apr 11, 416(6881): 603-7.
*Nature News & Views 2002; 416: 595-598.
*Nature Immunology News & Views 2002; 3(5): 423-424.
*Nature Reviews Immunology Highlights 2002; 2: 302.
*Faculty of 1000 Exceptional Selection, factor 9.9
*Trends in Pharmacologic Sciences News and Comment 2002. 23(6): 257.
*BioWorld Today, How Chloroquine works against Autoimmune diseases: Toll-like receptor blocker potential cure 2002; 13(69): 1.
*B.U. Bridge Research briefs 2002; V(31): 2.
*MedCenter News Research in brief 2002; May, p. 4.
- Rifkin IR*, Leadbetter EA*, Beaudette B, Kiani C, Monestier M, Shlomchik MJ, Marshak-Rothstein A. Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells. J Immunol 2000; 165: 1226-33.*contributed equally.
- Leadbetter EA, Bourque C, Devaux B, Sunshine G, Hirani S, Wallner B, Smilek D, Happ MP.Experimental Autoimmune Encephalomeyelitis induced with a combination of MBP and MOG is ameliorated by the administration of a single MBP peptide. J Immunol 1997; 161(1): 504-12.
- Frye C and Leadbetter E. 5alpha reduced progesterone metabolites are essential in the hamster VTA for sexual receptivity. Life Sciences 1994; 54(10): 653-59.