Effector functions of mucosal associated invariant T cells in response to viral infections and vaccines

The rapid propagation of host immune responses following nucleic-acid sensing is necessary for protection against viruses and vaccines. Cytokines, such as type I interferon (IFN), play a key role. Mucosal Associated Invariant T (MAIT) cells and related CD161+ innate-like lymphocytes are exquisitely sensitive to anti-viral cytokines and can trigger rapid effector functions such as IFN-γ production, which is important for protection. The aim of this thesis is to investigate whether human MAIT cells and related CD161+ lymphocytes respond to novel nucleic-acid based Adenoviral vectored (AdV) and mRNA vaccines, and understand how this might occur.
First, I show that CD161+ lymphocytes, which include MAIT cells, Vδ2+ γδ T cells, and NK cells, are the main producers of early IFN-γ in response to ChAdOx1-GFP infection of human peripheral blood mononuclear cells (PBMC) in vitro. These cells are activated by AdV-derived type I IFN, IL-18, and TNF. Although innate-like lymphocytes rapidly upregulate CD69 expression in response to type I IFN produced by plasmacytoid dendritic cells (pDCs), IFN-γ production requires monocyte-derived IL-18 and TNF.
Next, a longitudinal cohort study of healthcare workers (HCW) was used to understand the early immune response following SARS-CoV-2 AdV and mRNA vaccines. I show that early IFN-γ production after ChAdOx1-S prime is mainly due to cytokine-mediated innate-like lymphocyte activation, and is less prominent after boost. In contrast, enhanced IFN-γ production after BNT162b2 boost is associated with adaptive immune measures at the time of immunisation, and is reduced with extended dosing intervals. In vitro experiments show that IFN-γ dependent IFN-γR1 signalling can amplify early innate-like lymphocyte-derived IFN-γ production, which may influence the reactogenicity and immunogenicity of vaccine schedules.
Finally, I examine the early immune response in Inflammatory Bowel Disease (IBD) patients on biologic therapy targeting TNF, a key cytokine for type I IFN-dependent IFN-γ production. The baseline circulating innate-like lymphocytes of IBD patients are distinct from healthy controls, with higher frequencies of Vδ2+ γδ T cells in patients receiving anti-TNF compared to those receiving anti-integrin therapy. Similarly, early IFN-γ generated after ChAdOx1-S prime is lower in IBD patients on anti-TNF, with no difference in type I IFN production. In vitro experiments show that anti-TNF reduces Ad-V induced pDC maturation, maintaining type I IFN production, but reduces monocyte-derived IL-18.
Overall, this thesis provides an insight into the early immune response to SARS-CoV-2 vaccines and highlights the role of cytokines, especially IFNs, and adaptive immunity in amplifying MAIT cell responses to novel vaccines. These findings raise questions about how environmental factors, like prior infections and the tissue cytokine milieu, may regulate immune responses, and the significance of innate-like lymphocytes to the variability of human immune responses.

Keywords: immune response regulation
interferons
adenoviral vectored vaccines
mRNA vaccines
MAIT cells
human immunology
early immune response
Advisor: Klenerman, P
Provine, N
Uhlig, H