Parasitology Seminar Series
Title: "Toxoplasma gondii and the adaptive immune system – new interactions revealed by genetic screens"
Speaker: Kirk Jensen, PhD
Assistant Professor, School of Natural Sciences
University of California, Merced
Date: June 10, 2019
Time: 12-1 pm
131 Hill Pavilion
University of Pennsylvania School of Veterinary Medicine
380 S University Avenue, Philadelphia, PA 19104
Parasites are masters of immune evasion, and as such, the generation of a protective vaccine for human parasitic pathogens has been met with many setbacks. Using parasite and mouse genetic screens, my current work explores the interface between T. gondii and the adaptive immune system. We have learned that T. gondii uses multiple polymorphic virulence factors to manipulate CD8 T cell activation and evade of immunological memory responses generated in primed mice. These results underscore the difficulty in achieving sterile immunity to protozoan pathogens and suggest T. gondii is more dangerous than previously appreciated, especially strains from South America. We have also uncovered new requirements for immunity to highly virulent strains. Unlike susceptible C57BL/6J mice, we noted A/J mice were highly resistant to secondary infection and therefore, determined resistance loci that segregated within 26 recombinant inbred (AxB,BxA) lines. The QTL with largest effect encodes a highly polymorphic gene, Nfkbid, and found that Nfkbid null mice (bumble) were susceptible to secondary, but not primary infection. Bumble mice had intact memory T cell responses, but failed to generate parasite-specific IgM and were defective in producing most parasite-specific IgG isotypes following infection. Nfkbidencodes IκBNS, which belongs to a family of nuclear NF-κB regulators, and is required for B-1 cell development and T-independent antibody responses. Consistent with this, we estimate nearly 70% of the antibody repertoire in primed mice requires intact glycophosphatidylinositol (GPI)-anchors for recognition of T. gondii antigen. Importantly, the GPI anchor covers the surface of most protozoan parasites and is a known B-1 cell antigen. Taken together, we propose a model in which T cell-mediated immunity to T. gondii must be ‘layered’ with Nfkbid-driven B-1 cell responses to the GPI-anchor of T. gondii. Antibody responses to non-protein antigens may be fundamental for immunity to most parasites, and in theory, should be targeted in parasite vaccines.
Dr. Jensen has over 19 years of experience in the fields of immunology and host-parasite interactions. His graduate work in the laboratories of Eli Sercarz (La Jolla Institute of Allergy and Immunology, Masters) and Yueh-hsiu Chien (Stanford School of Medicine, Ph.D.) exposed him to many issues surrounding T cell immunology. The central theme of his early work was that TCR engagement with antigen changed the functional outcome of T cell responses and their development. In particular, his doctoral work had a major impact in the field of γδ T cell biology, where he showed that during thymic development ‘antigen experienced’ cells became IFNγ produces while ‘antigen naïve’ cells produced IL-17, uniquely positioning them for inflammatory regulation. For his postdoctoral work, Dr. Jensen joined the laboratory of Jeroen Saeij (MIT) where he studied the effect of Toxoplasma gondii virulence factors on immune function. Over the past 4 years as an Assistant Professor at University of California, Merced, Dr. Jensen has established independent research studying the intersection between the adaptive immune system and virulence factors of T. gondii.