Abstract
In order to orchestrate immune responses to a wide variety of pathogenic stimuli, CD4+ T- cells must integrate a variety of signals from conventional dendritic cells (cDCs), including recognition of presented antigenic peptides, costimulatory molecules, and soluble mediators. Along with the recognition of its specific antigenic peptide, the additional signals provided by the cDC inform the CD4+ T-cell how to respond to the presented antigen. More specifically, this can influence the extent to which CD4+ T-cells divide and expand their populations, the cytokines produced by the responding CD4+ T-cells, and the roles that they play as effector (TEFF) or follicular helper CD4+ T-cells (TFH).
Type I Interferons (IFN-I) are a group of cytokines involved in viral immunity that have been shown to programme cDCs to initiate T-helper type 2 (TH2) responses. Whether IFN-I promotes CD4+ T-cell differentiation or expansion, and the signals IFN-I induces in cDCs to promote TH2 development have not been established.
Another cytokine important for the priming and expansion of TH2 cells is IL-4. Although this cytokine has been shown to stimulate the development of TH2 cells in vitro, in vivo the role of IL-4 is not as clear, as it is not produced by cDCs following exposure to TH2 antigens such as helminths and allergens nor has it been shown to be needed for TH2 priming. IL-4 can also facilitate the expansion of non-TH2 T-cell subsets, calling into question its role in specifically inducing TH2 immunity.
This thesis set out to distinguish the roles of IFN-I signalling in cDC2, and IL-4 signalling in CD4+ T-cells as cytokines that facilitate CD4+ T-cell expansion, or as signals that facilitate CD4+ T-cell differentiation into cytokine-producing subsets in vivo. In order to do this, a murine CD4+ T-cell adoptive transfer model was devised, using donor cells labelled with division dyes to investigate CD4+ T-cell expansion, followed by intradermal administration of inactivated Nippostrongylus brasiliensis, and the analysis of the CD4+ T-cell response in the draining lymph node (LN).
Using this model, this thesis found that IFN-I conditioning of cDC primarily acts to facilitate CD4+ T-cell expansion, leading to an increase in both TH2 and TFH cells. Adoptive transfer models were also used to demonstrate that IL-4 can increase the differentiation and expansion of TH2 cells, as well as increase the expansion of TH1 cells independently to its role in TH2 priming. Finally, using a mixed bone marrow chimeric mouse model, IL-4 was demonstrated to be critical for the maintenance of the developing TH2 response, but not for initial TH2 priming.
Together, results in this thesis demonstrate how cDC conditioning and cytokine signalling in CD4+ T-cells can act in a context-dependent manner to influence both CD4+ T-cell differentiation and expansion.