Open Access Te Herenga Waka-Victoria University of Wellington
Browse
thesis_access.pdf (11.85 MB)

Understanding the Generation and Regulation of IL-4 Producing T Helper 2 Cells

Download (11.85 MB)
thesis
posted on 2021-11-12, 15:36 authored by Mearns, Helen

A keenly sought therapeutic approach for the treatment of allergic disease is the identification and neutralization of the cytokine that regulates the differentiation of Th2 cells. Th2 cells are CD4 T cells differentiated to secrete IL-4. These cells are exciting new targets for asthma therapies due to the key role they play in allergic airway diseases. Recently the cytokine IL-25 has been shown to enhance Th2 cell activity and play important roles in mediating allergic inflammatory responses. To investigate this further we crossed IL-25 deficient mice with GFP-IL-4 reporter mice and developed an assay of in vitro and in vivo IL-4 independent Th2 differentiation. These assays were used to determine whether IL-25 was critical for the formation of Th2 cells. We found there was no physiological role for IL-25 in either the differentiation of Th2 cells or their development to effector or memory Th2 subsets. In the strong Th2 setting of a helminth infection the absence of IL-25 resulted in no defects in the effector type 2 responses associated with T helper type 2 immunity including, mucous hyperplasia, class switching to IgE and protection against challenge infections. Importantly this data challenges the newly found and growing status of the cytokine IL-25 and its proposed role in promoting Th2 responses. The second part of this thesis investigated whether the genomic organisation, which reflects commitment to Th2 cytokine expression, could provide a clearer definition of a functional in vivo Th2 cell. Two distinct IL-4 reporter mice were crossed and Th2 in vivo assays were developed that allowed tracking of the individual alleles of IL-4 in a variety of tissue types and Th2 subsets. Interestingly in vivo expression of IL-4 is mostly monoallelic yet there is a small highly activated population of biallelic IL-4 expressing Th2 cells. Physiologically each allele of IL-4 was required for a functional Th2 response with total serum IgE titres up to 4 fold lower in IL-4+/- heterozygous compared to the IL-4+/+ sufficient animals and a significant loss in protective immunity against challenge infections with helminths occurred in the IL-4+/- heterozygous animals. The similarity in deficiencies in Th2 immunity in the IL-4+/- heterozygous and IL-4-/- deficient compared to the IL-4+/+ sufficient animals lead to the proposal that the generation of biallelic Th2 cells may be required for specialised cell-to-cell mediated delivery of tailored activation signals and higher quantities of IL-4 required to mediate fully developed Th2 immune responses.

History

Copyright Date

2012-01-01

Date of Award

2012-01-01

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Biomedical Science

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Biological Sciences

Advisors

Le Gros, Graham; Ronchese, Franca