Role of TSLP in Dendritic Cell Programming during Allergic Responses

Abstract

Allergic diseases such as atopic dermatitis (AD), asthma and allergic rhinitis are among the most common chronic illnesses around the world. Although they cause significant discomfort to those affected, effective treatments are currently not available. Allergic diseases are governed by the activity of a T helper cell subpopulation termed type 2 T helper cell (Th2 cell); however, the factors that are involved in initiation of Th2 cell development are not fully elucidated. For development of effective therapies, a better understanding of Th2 development is required.

Thymic stromal lymphopoietin (TSLP), expressed in lesional skin of AD patients, has emerged as one of the candidate molecules for initiating or sustaining Th2 immune responses through activation of dendritic cells (DC).

Previous investigations of murine skin allergy models have demonstrated that keratinocytes produce TSLP following topical applications of a vitamin D3 analogue, MC903, leading to an AD-like inflammation. Topical application of another chemical called dibutyl-phthalate (DBP) has also been shown to trigger TSLP production and pathologies associated with human skin allergy. However, the mechanism by which TSLP triggers allergic responses is not well understood. In this thesis, I used TSLP- reporter and TSLP receptor (TSLPR)-knock-out (KO) mice to evaluate the TSLP dependency of T cell responses triggered by skin allergy models.

This thesis shows that topical application of MC903 or DBP with antigens, triggers TSLP expression by keratinocytes and TSLP-dependent Th2 T cell responses in draining lymph nodes. In contrast, it also shows that the Th2 responses triggered by skin exposure to model antigens such as house dust mite (HDM) and Nippostrongylus brasiliensis (Nb.) are TSLP-independent.

Using DC depletion models and bone marrow chimeric mice, I showed that a subset of skin MHC-IIhi DC termed ‘triple negative’ or TN DC were likely to be involved in the TSLP-dependent Th2 responses, whereas another skin DC termed CD11bhi DC were likely to be involved in the TSLP-independent Th2 responses. In this thesis, RNA sequencing experiments were performed to initiate a detailed molecular characterisation of DC during TSLP-dependent Th2 responses. The RNA sequencing experiments have revealed some potential targets to block TSLP-dependent Th2 responses.

This thesis shows that Th2 responses can be triggered in TSLP-dependent or -independent manners and they are likely to be governed by different DC subsets. The implications of the findings in the context of currently available publications and therapies for allergic diseases will be discussed.