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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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| Summary: | 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. |
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