Repertoire selection and effector differentiation during NKT cell development

Abstract

Natural killer T (NKT) cells are innate-like lymphocytes that develop and mature in the thymus. From there, they home to the peripheral lymphoid tissues where, in some cases, they can finalise the maturation program. NKT cells function by close cell-cell interactions with antigen presenting cells and upon activation release copious amounts of proinflammatory and immunoregulatory cytokines and chemokines. NKT cells acquire their functions during development. I address two questions in this dissertation: (a) the role of negative selection in sculpting a functional NKT cell repertoire; and (b) the role of interleukin (IL)-15 in NKT cell effector differentiation and homeostasis. My studies generated mouse models for overt or impaired negative selection and revealed direct evidence for negative selection in sculpting the semi-invariant T cell receptor repertoire of NKT cells. Nonetheless, the effect of negative selection, as probed using currently known NKT cell agonists, was subtle in that it had modest effects on NKT cell function. The most significant advance I made is related to an understanding of cytokine signals that induce NKT cell effector differentiation and how these signals are integrated to affect this outcome. I discovered that IL-15 plays a pivotal role in signalling NKT cell survival through the induction of Bcl-2 family member Bcl-xL. Rescue of NKT cell development by enforced Bcl-xL expression in IL-15 deficient mouse thymocytes exposed an additional role of IL-15 in inducing terminal maturation and effector differentiation of NKT cells. Gene expression analysis indicated that IL-15 regulated Tbx21 (T-bet) expression and that of T-bet-regulated genes, including those that mediate effector functions of NKT cells. Because T-bet was previously shown to regulate terminal maturation and effector differentiation of NKT cells, I conclude that IL-15 mediates its functions within NKT cells at least in part through regulated expression of T-bet. Thus, my findings have revealed important new insights into signals that regulate the development of functional NKT cells.