Biology subjects

Jensen, K. D. C.

Publications and source records attributed to Jensen, K. D. C..

3 recordsLinked to original sources

bioRxiv2024

The GPI sidechain of Toxoplasma gondii prevents parasite pathogenesis

Glycosylphosphatidylinositols (GPIs) are highly conserved anchors for eukaryotic cell surface proteins. The apicomplexan parasite, Toxoplasma gondii, is a widespread intracellular parasite of warm-blooded animals whose plasma membrane is covered with GPI-anchored proteins, and free GPIs called GIPLs. While the glycan portion is conserved, species differ in sidechains added to the triple mannose core. The functional significance of the Glc1,4GalNAc{beta}1-sidechain reported in Toxoplasma gondii has remained largely unknown without an understanding of its biosynthesis. Here we identify and disrupt two glycosyltransferase genes and confirm their respective roles by serology and mass spectrometry. Parasites lacking the sidechain on account of deletion of the first glycosyltransferase, PIGJ, exhibit increased virulence during primary and secondary infections, suggesting it is an important pathogenesis factor. Cytokine responses, antibody recognition of GPI-anchored SAGs, and complement binding to PIGJ mutants are intact. In contrast, the scavenger receptor CD36 shows enhanced binding to PIGJ mutants, potentially explaining a subtle tropism for macrophages detected early in infection. Galectin-3, which bind GIPLs, exhibits a slight enhancement of binding to PIGJ mutants, and the protection of galectin-3 knockout mice from lethality suggests that{Delta} pigj parasite virulence in this context is sidechain dependent. Parasite numbers are not affected by{Delta} pigj early in the infection in wildtype mice, suggesting a breakdown of tolerance. However, increased tissue cysts in the brains of mice infected with{Delta} pigj parasites indicate an advantage over wildtype strains. Thus, the GPI sidechain of T. gondii plays a crucial and diverse role in regulating disease outcome in the infected host. SummaryThe functional significance of sidechain modifications to the GPI anchor is yet to be determined because the glycosyltransferases responsible for these modifications have not been identified. Here we present identification and characterization of both T. gondii GPI sidechain-modifying glycosyltransferases. Removal of the glycosyltransferase that adds the first GalNAc to the sidechain results in parasites without a sidechain on the GPI, and increased parasite virulence. Loss of the second glycosyltransferase results in a sidechain with GalNAc alone, and no glucose added, and has negligible effect on parasite virulence. This indicates GPI sidechains as fundamental to host-parasite interactions.

microbiology↗

bioRxiv2023

T cell exhaustion dynamics in systemic autoimmune disease

Unlike in infection and cancer, T cell exhaustion in autoimmune disease has not been clearly defined. Here we set out to understand inhibitory protein (PD-1, Tim3, CTLA4, Lag3) expression in CXCR5- and CXCR5+ CD8 and CD4 T cells in systemic lupus erythematosus. CXCR5+ CD8 and CD4 T cells express PD-1 and engage B cells in germinal center reactions, leading to autoantibody formation in autoimmunity. We hypothesized that CXCR5+ CD8 T cells develop an exhausted phenotype as SLE autoimmunity expands from initial to chronic, self-perpetuating disease due to chronic self-antigen exposure. Our results indicate that there is no exhaustion frequency differences between sexes, although disease kinetics vary by sex. CXCR5+ CD8 T cells express primarily IFN{gamma}, known to promote autoimmune disease development, whereas CXCR5-CD8 T cells express TNF and IFN{gamma} as disease progresses from 2-6 months. Tim3 is the highest expressed inhibitory marker for all CD4 and CD8 T cell populations demonstrating potential for terminally exhausted populations. CTLA4 expression on CD4 T cells suggests potential tolerance induction in these cells. We identified exhaustion phenotypes within autoimmune disease that progress with increasing lupus erythematosus severity and possibly provide a feedback mechanism for immunological tolerance. HighlightsO_LICXCR5- and CXCR5+ CD8 T cells expand with rate of disease in SLE mouse model. C_LIO_LICXCR5+ CD8 T cells are low contributors to TNF disease progression unlike CXCR5-CD8 T cells but may increase disease mechanisms through high IFN{gamma} production. C_LIO_LIInhibitory markers upregulate in frequency with the highest amounts seen in Tim3+ populations. Tim3+Lag3+ expression may be an indicator of terminal differentiation for all populations. C_LIO_LIInhibitory marker expression frequency was unrelated to sex. C_LI

immunology↗

bioRxiv2018

T cell and peripheral blood parameters define progression of autoimmune disease in the IL-2Rα KO model

IL-2R is required to generate the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. Mice deficient in IL-2R (IL-2R-KO) develop systemic autoimmune disease and die from severe anemia between 18-80 days of age. These mice develop kinetically differing autoimmune disease, with approximately a quarter dying by 21 days of age and half dying after 30 days. This research aims to define immune parameters that distinguish cohorts of mice that develop early- and late-stage autoimmune disease in the IL-2R-KO genetic background. To investigate these differences, we evaluated complete blood counts (CBC), antibody binding of RBCs, T cell numbers and activation, and hematopoietic progenitor changes, to assess the extent of peripheral autoimmune hemolytic anemia and bone marrow failure. Early onset disease correlated with anti-RBC antibodies and lower hematocrit on day 19. We also found that predicted late stage-disease IL-2R-KO mice have higher numbers of developing memory CD4 and CD8 T cells and reduced AIHA at early ages. The expansion of CD8 T cells seen in IL-2R -KO mice is driven by unimpaired IL-2 signaling which correlated with increased IL-2RP expression. Using a simple CBC we were able to predict disease kinetics to explore mechanisms underlying early and late disease.

immunology↗