Title: Invariant Natural Killer T cell activation by fungi
Description: Invariant Natural Killer T (iNKT) cells are innate-like T lymphocytes recognizing self and foreign lipid antigens presented by CD1d, a trans-membrane glycoprotein closely related to MHC molecules. iNKT cells become rapidly activated during infection and play an important role in immunity against a spectrum of microbes. Unlike MHC-restricted T cells, however, iNKT cells express a semi-clonal T cell receptor (TCR) repertoire, comprised of a canonical Vα chain paired with a limited set of Vβ chains. Furthermore, in contrast to MHC, CD1d is non-polymorphic. This suggests that the diversity of antigens that can be presented to and recognized by iNKT cells may be limited. Clarifying the mechanisms allowing iNKT cells to respond to different microbes is central to understanding the biology of these and other innate-like lymphocytes with restricted receptor diversity. In this dissertation, we address this question in the context of infection with fungi, a neglected class of pathogens with increasing clinical significance.

Using a model of pulmonary infection with the filamentous fungus Aspergillus fumigatus , we find that mice lacking CD1d-restricted T cells are impaired in their ability to control the infection. Consistent with this observation, iNKT cells mount a rapid anti-fungal response in the airways of infected mice. We dissect the mechanism driving iNKT cell activation by A. fumigatus using primary murine iNKT cell lines, a powerful new tool the derivation and characterization of which is also described here (Chapter 1), and define a novel and broadly applicable mechanism whereby innate recognition of ubiquitous fungal cell wall polysaccharides called β-glucans by APCs expressing the C-type lectin Dectin-1 drives anti-fungal iNKT cell activation, bypassing the need for cognate recognition of fungal lipid antigens (Chapter 2). Finally, we discuss the initial results from our contribution to the Immunological Genome Project (ImmGen), a laboratory consortium whose goal is to generate a publicly available compendium of whole genome expression data for all immune cell subsets. By comparing the expression profiles of iNKT cells from different organs to each other and to other immune cells, we begin defining unique features of iNKT cells and iNKT cell subsets (Chapter 3).