Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis

Simple item page
dc.contributor.advisorHurdayal, Ramona
dc.contributor.advisorBrombacher, Frank
dc.contributor.authorMaine, Rebeng
dc.date.accessioned2021-01-15T09:53:11Z
dc.date.available2021-01-15T09:53:11Z
dc.date.issued2020
dc.description.abstractIn a murine model of Leishmania major infection, susceptible BALB/c mice develop a detrimental Type 2 immune response characterized by the production of interleukin (IL)-4 and IL-13, which single through a common receptor, the IL-4 receptor alpha chain (IL-4Rα). Forkhead box P3 (Foxp3⁺) Regulatory T (Treg) cells are an unique subset of CD4⁺ T cells that play important immunomodulatory roles maintaining a balance between Type 1 and Type 2 immune responses. During L. major-induced cutaneous leishmaniasis, Treg cells accumulation at the site of infection has been implicated in suppressing a detrimental Type 2 immune response by modulating early interleukin (IL)-4 production, however it remains unclear if IL- 4Rα mediated signalling on Treg cells play a significant role in this process. To investigate this further, a novel BALB/c model was utilized in which the IL-4Rα chain was conditionally knocked out on Treg cells (Foxp3ᶜʳᵉIL-4Rα⁻<sup>/</sup>ˡᵒˣ mice). We demonstrated that the differential IL- 4Rα deletion efficiency in male (approximately 102 %) and female (approximately 32%) was maintained during L. major infection. Foxp3ᶜʳᵉIL-4Rα⁻<sup>/</sup>ˡᵒˣ male mice, which had a greater degree of IL-4Rα deletion on Foxp3⁺ Treg cells, developed significant footpad swellings and ear swellings, increased parasitic burdens at the site of infection and within draining lymph nodes. This hypersusceptible phenotype observed in Foxp3ᶜʳᵉIL-4Rα⁻<sup>/</sup>ˡᵒˣ BALB/c male mice was accompanied with an increased Treg cell activity and amplified Type-2 immune response with an increase in IL-4, IL-10 from L. major-infected lymph node samples and IgE antibody secretion in L. major infected serum samples. Flow cytometry analysis revealed that a L. major-induced Indoleamine 2,3 dioxygenase (IDO)-mechanism could allow for increased Leishmania replication. Collectively, these data suggest a protective role for IL-4Rα signalling on Treg cells in suppressing a detrimental Type 2 during cutaneous leishmaniasis.
dc.identifier.apacitationMaine, R. (2020). <i>Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis</i>. (Master Thesis). University of Cape Town. Retrieved from http://hdl.handle.net/11427/32532en_ZA
dc.identifier.chicagocitationMaine, Rebeng. <i>"Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis."</i> Master Thesis., University of Cape Town, 2020. http://hdl.handle.net/11427/32532en_ZA
dc.identifier.citationMaine, R. 2020. Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis. Master Thesis. University of Cape Town. http://hdl.handle.net/11427/32532en_ZA
dc.identifier.ris TY - Master Thesis AU - Maine, Rebeng AB - In a murine model of Leishmania major infection, susceptible BALB/c mice develop a detrimental Type 2 immune response characterized by the production of interleukin (IL)-4 and IL-13, which single through a common receptor, the IL-4 receptor alpha chain (IL-4Rα). Forkhead box P3 (Foxp3⁺) Regulatory T (Treg) cells are an unique subset of CD4⁺ T cells that play important immunomodulatory roles maintaining a balance between Type 1 and Type 2 immune responses. During L. major-induced cutaneous leishmaniasis, Treg cells accumulation at the site of infection has been implicated in suppressing a detrimental Type 2 immune response by modulating early interleukin (IL)-4 production, however it remains unclear if IL- 4Rα mediated signalling on Treg cells play a significant role in this process. To investigate this further, a novel BALB/c model was utilized in which the IL-4Rα chain was conditionally knocked out on Treg cells (Foxp3ᶜʳᵉIL-4Rα⁻<sup>/</sup>ˡᵒˣ mice). We demonstrated that the differential IL- 4Rα deletion efficiency in male (approximately 102 %) and female (approximately 32%) was maintained during L. major infection. Foxp3ᶜʳᵉIL-4Rα⁻<sup>/</sup>ˡᵒˣ male mice, which had a greater degree of IL-4Rα deletion on Foxp3⁺ Treg cells, developed significant footpad swellings and ear swellings, increased parasitic burdens at the site of infection and within draining lymph nodes. This hypersusceptible phenotype observed in Foxp3ᶜʳᵉIL-4Rα⁻<sup>/</sup>ˡᵒˣ BALB/c male mice was accompanied with an increased Treg cell activity and amplified Type-2 immune response with an increase in IL-4, IL-10 from L. major-infected lymph node samples and IgE antibody secretion in L. major infected serum samples. Flow cytometry analysis revealed that a L. major-induced Indoleamine 2,3 dioxygenase (IDO)-mechanism could allow for increased Leishmania replication. Collectively, these data suggest a protective role for IL-4Rα signalling on Treg cells in suppressing a detrimental Type 2 during cutaneous leishmaniasis. DA - 2020 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PY - 2020 T1 - Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis TI - Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis UR - http://hdl.handle.net/11427/32532 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/32532
dc.identifier.vancouvercitationMaine R. Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis. [Master Thesis]. University of Cape Town, 2020 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/32532en_ZA
dc.language.isoeng
dc.publisherUniversity of Cape Town
dc.publisher.departmentDepartment of Molecular and Cell Biology
dc.publisher.facultyFaculty of Science
dc.subject.otherMolecular and Cell Biology
dc.titleInvestigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMSc
uct.type.publicationResearch
uct.type.resourceMaster Thesis
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
thesis_sci_2020_maine_rebeng.pdf
Size:
3.47 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Masters