Institutionen för medicin, Huddinge Sjukhus / Department of Medicine at Huddinge University Hospital
Abstract
Invariant natural killer T (NKT) cells are innate-like lymphocytes with
both immunoregulatory and cytotoxic functions that play a role as
activators and regulators of the immune response in many diseases. NKT
cells are believed to bridge the innate and adaptive immune systems by
rapidly producing large quantities of cytokines after recognition of
CD1d-presented lipid antigens. NKT cells can be divided into two
phenotypically and functionally distinct subsets based on the expression
of CD4. How the NKT cells and their subsets are regulated, and how they
integrate signals from their environment to modulate immune responses is
still not fully understood.
In this thesis I have investigated how the activity of NKT cells can be
modulated by factors other than the TCR, such as cell surface receptors
and cytokines. These investigations have been based on blood samples from
healthy controls, and from patients suffering from HIV-1 infection or
atopic eczema (AE). We have found that CD4- NKT cells are able to
degranulate and kill target cells in an NKG2D-dependent but
TCR-independent manner in response to NKG2D stimulus. Moreover, we have
shown that NKG2D+ NKT cells frequently express perforin that polarizes
toward NKG2D-ligand expressing tumor cells. These data demonstrate that
the CD4- subset of human NKT cells can mediate direct lysis of
CD1d-negative target cells upon NKG2D engagement. We have further
characterized the phenotype and function of NKT cells in patients with
chronic diseases. In patients with chronic HIV- 1 infection, the CD4- NKT
cell subset showed increased expression of the inhibitory programmed
death-1 (PD-1) receptor, and displayed severe functional defects.
However, the functional impairment was not caused by PD-1 expression per
se because the defect could not be reversed by PD-1 blockade. In
addition, we have studied the effect of interleukin-2 (IL-2) on NKT cells
and natural killer (NK) cells in patients with chronic HIV-1 infection.
Material for this study was obtained from a longitudinally study, where
administration of IL-2 was added to the antiretroviral treatment (ART)
for one year. We found that NKT cells and NK cells responded with
different kinetics and in different ways to the IL-2 administration. The
NKT cells responded with a gradual numerical increase, but with no
significant functional changes. NK cells responded rapidly with an
expansion of the cytotoxic CD56dim NK cell subset and increased IFN-γ
production. However, the effects of IL-2 on these cells were generally
not sustained post treatment. NKT cells were also studied in the chronic
inflammatory skin disease AE where the patients have elevated levels of
plasma IL-18. Our data provide evidence that IL-18 is a potent activator
of human NKT cells promoting an acute pro-inflammatory CD1d-dependent
response, even in the absence of exogenous lipid antigens. Interestingly,
chronic exposure of NKT cells to IL-18 is inhibitory and skews the NKT
cell pool by selectively suppressing the proliferation of CD4+ NKT cells.
Importantly, our in vitro data are reflected in AE patients where reduced
numbers of CD4+ NKT cells are associated with elevated levels of IL-18
and disease severity.
In conclusion, the work presented here contributes to our understanding
of the function and role of NKT cells in human diseases including
infections and allergie
