Role of MAIT cells in human antimicrobial immunity

Mucosa-associated invariant T (MAIT) cells are a relatively recently discovered subset of unconventional T cells. In humans, MAIT cells are predominantly CD8+CD4- (CD8+) with a smaller CD8-CD4- (double-negative, DN) subset, and they are abundant in the peripheral blood, liver, and mucosal tissues. MAIT cells recognize riboflavin metabolites produced by a wide range of bacteria and fungi, and presented by the evolutionarily conserved major histocompatibility complex (MHC) class I-related (MR1) protein. Given the novelty of MAIT cells, this thesis had the overall aim of advancing the knowledge of their immunobiology and antimicrobial immune responses.

In this thesis, we first established experimental platforms to study functions of MAIT cells in vitro, including activation, cytokine production, proliferation, cytotoxicity, as well as their ability to kill target cells. The established methodologies are versatile and can be adapted to answer a wide variety of MAIT cell-related questions. We next applied these experimental platforms to study MAIT cell responses to distinct riboflavin biosynthesis-competent microbes, and found them to differ in quality and quantity with the type and dose of microbe. We demonstrated that the TCR β chain composition and the expression of certain natural killer (NK)-cell associated receptors on MAIT cells shape their responses to TCR and innate cytokine stimulation, respectively, and thereby contribute to the functional compartmentalization of this cell population. In the third study, we dissected differences between CD8+ and DN MAIT cells with the aim of understanding the relationship between these subsets. CD8+ MAIT cells display superior functional capacity, consistent with their higher basal levels of co-stimulatory and cytotoxic molecules, and of classical effector transcription factors when compared with DN MAIT cells. Furthermore, DN MAIT cells accumulate during fetal development and their adult Vβ repertoire is a subset of that of CD8+ MAIT cells, suggesting that DN MAIT cells may derive from CD8+ MAIT cells in vivo. In the fourth study, we investigated MAIT cells in chronic hepatitis delta virus (HDV) infection. We found that MAIT cells are severely depleted from the peripheral blood of HDV-infected patients in comparison with chronic hepatitis B virus (HBV)-infected patients and healthy controls, and that MAIT cell loss is associated with the severity of liver fibrosis. Residual MAIT cells are activated, exhausted, and functionally impaired in response to TCR stimulation.

Altogether, the findings in this thesis advance our understanding of human MAIT cells as functionally heterogeneous T cells that display differential response patterns to microbes and to innate cytokines, and that are markedly affected in hepatitis delta. At the same time, these findings have given rise to numerous new questions to be addressed in the rapidly expanding field of MAIT cell research in the years to come.

List of scientific papers

I. Human MAIT-cell responses to Escherichia coli: activation, cytokine production, proliferation, and cytotoxicity. Joana Dias, Michał J. Sobkowiak, Johan K. Sandberg, and Edwin Leeansyah. Journal of Leukocyte Biology. 2016, 100: 233-240.
https://doi.org/10.1189/jlb.4TA0815-391RR

II. Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines. Joana Dias, Edwin Leeansyah, and Johan K. Sandberg. Proceedings of the National Academy of Sciences of the U S A. 2017, 114: E5434-E5443.
https://doi.org/10.1073/pnas.1705759114

III. Human CD8-negative MAIT cells are functionally distinct from CD8-positive MAIT cells. Joana Dias, Jean-Baptiste Gorin, Caroline Boulouis, Robin H. G. A. van den Biggelaar, Anna Gibbs, Liyen Loh, Douglas F. Nixon, Kristina Broliden, Annelie Tjernlund, Johan K. Sandberg, and Edwin Leeansyah. [Manuscript]

IV. Chronic hepatitis delta virus infection drives severe loss and functional exhaustion of MAIT cells. Joana Dias, Julia Hengst, Edwin Leeansyah, Sebastian Lunemann, David F. G. Malone, Svenja Hardtke, Tiphaine Parrot, Lena Berglin, Thomas Schirdewahn, Michael P. Manns, Markus Cornberg, Hans-Gustaf Ljunggren, Heiner Wedemeyer, Johan K. Sandberg, and Niklas K. Björkstrom. [Manuscript]