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Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis
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...
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| Format: | Thesis |
| Language: | English |
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University of Cape Town
2021
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| _version_ | 1867613908478459904 |
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| access_status_str | Open Access |
| author | Maine, Rebeng |
| author2 | Hurdayal, Ramona |
| author_browse | Hurdayal, Ramona Maine, Rebeng |
| author_facet | Hurdayal, Ramona Maine, Rebeng |
| author_sort | Maine, Rebeng |
| collection | Thesis |
| description | 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. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/32532 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:43:37.479Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | University of Cape Town |
| publisherStr | University of Cape Town |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/32532 Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis Maine, Rebeng Hurdayal, Ramona Brombacher, Frank Molecular and Cell Biology 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. 2021-01-15T09:53:11Z 2021-01-15T09:53:11Z 2020 Master Thesis Masters MSc http://hdl.handle.net/11427/32532 eng application/pdf University of Cape Town Department of Molecular and Cell Biology Faculty of Science |
| spellingShingle | Molecular and Cell Biology Maine, Rebeng Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis |
| thesis_degree_str | Master's |
| title | Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis |
| title_full | Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis |
| title_fullStr | Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis |
| title_full_unstemmed | Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis |
| title_short | Investigating the role of IL-4Rα mediated signalling on Foxp3⁺ T regulatory cells during cutaneous leishmaniasis |
| title_sort | investigating the role of il 4rα mediated signalling on foxp3⁺ t regulatory cells during cutaneous leishmaniasis |
| topic | Molecular and Cell Biology |
| url | http://hdl.handle.net/11427/32532 |
| work_keys_str_mv | AT mainerebeng investigatingtheroleofil4ramediatedsignallingonfoxp3tregulatorycellsduringcutaneousleishmaniasis |