Abstract
CD1d-restricted invariant natural killer T (iNKT) cells have diverse immune stimulatory/regulatory activities through their ability to release cytokines and to kill or transactivate other cells. Activation of iNKT cells can protect against multiple diseases in mice but clinical trials in humans have had limited impact. Clinical studies to date have targeted polyclonal mixtures of iNKT cells and we proposed that their subset compositions will influence therapeutic outcomes. We sorted and expanded iNKT cells from healthy donors and compared the phenotypes, cytotoxic activities and cytokine profiles of the CD4+, CD8α+ and CD4−CD8α− double-negative (DN) subsets. CD4+ iNKT cells expanded more readily than CD8α+ and DN iNKT cells upon mitogen stimulation. CD8α+ and DN iNKT cells most frequently expressed CD56, CD161 and NKG2D and most potently killed CD1d+ cell lines and primary leukemia cells. All iNKT subsets released Th1 (IFN-γ and TNF-α) and Th2 (IL-4, IL-5 and IL-13) cytokines. Relative amounts followed a CD8α>DN>CD4 pattern for Th1 and CD4>DN>CD8α for Th2. All iNKT subsets could simultaneously produce IFN-γ and IL-4, but single-positivity for IFN-γ or IL-4 was strikingly rare in CD4+ and CD8α+ fractions, respectively. Only CD4+ iNKT cells produced IL-9 and IL-10; DN cells released IL-17; and none produced IL-22. All iNKT subsets upregulated CD40L upon glycolipid stimulation and induced IL-10 and IL-12 secretion by dendritic cells. Thus, subset composition of iNKT cells is a major determinant of function. Use of enriched CD8α+, DN or CD4+ iNKT cells may optimally harness the immunoregulatory properties of iNKT cells for treatment of disease.
Highlights
Invariant natural killer T cells are cytotoxic T lymphocytes that express NK cell markers and a T cell receptor (TCR) composed of an invariant a-chain (Va24Ja18 in humans and Va14Ja18 in mice) paired with one of a limited number of bchains. iNKT cells recognize glycolipid antigens presented by the major histocompatibility complex class I-like molecule CD1d [1,2]
The importance of iNKT cells in the prevention of disease and as potential therapeutic targets was first recognized with observations that mice lacking CD1d or iNKT cells are predisposed to developing cancer, autoimmune and infectious disease [6,51] and with the discovery of a-GalCer and its beneficial effects in murine models of disease [5,18,19,20]
The promising results in murine models have led to clinical trials in humans with various cancers, involving i.v. injection of a-GalCer [29] or a-GalCer-pulsed antigen-presenting cells (APC) [26,30]
Summary
Invariant natural killer T (iNKT) cells are cytotoxic T lymphocytes that express NK cell markers and a T cell receptor (TCR) composed of an invariant a-chain (Va24Ja18 in humans and Va14Ja18 in mice) paired with one of a limited number of bchains. iNKT cells recognize glycolipid antigens presented by the major histocompatibility complex class I-like molecule CD1d [1,2]. INKT cells recognize glycolipid antigens presented by the major histocompatibility complex class I-like molecule CD1d [1,2]. They can recognize a number of self and bacterial glycolipids [3,4] but the most potent activator of iNKT cells known to date is the marine sponge-derived glycolipid agalactosylceramide (a-GalCer) [5]. Therapeutic activation of iNKT cells in murine models can prevent tumor growth, ameliorate autoimmune disease and protect against microbial infection [6,18,19,20]. Numerical and functional iNKT cell deficiencies have been reported in a number of human diseases [21,22,23,24,25], but clinical trials that have targeted iNKT cells in humans have to date been somewhat disappointing [26,27,28,29,30]
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