CD1d-unrestricted human NKT cells release chemokines upon Fas engagement

Abstract

Attempts at inducing allograft immune privilege by enforced Fas ligand expression have shown accelerated rejection mediated by neutrophils. While it has been proposed that Fas ligand was directly chemotactic toward neutrophils, several lines of evidence argue for an indirect recruitment mechanism. This question was addressed by using in vitro migration assays that used highly purified human leukocyte subsets. IntroductionApoptosis plays a crucial role in development, tissue homeostasis, and immune system function. Fas-mediated apoptosis occurs through receptor oligomerization by Fas ligand (FasL), 1 leading to the recruitment of caspase-8. The auto-proteolytic activation of caspase-8 leads to executor caspase processing that, in turn, cleaves proteins essential for cell survival. Apoptotic cells are then engulfed by neighboring cells, limiting inflammation. 1 FasL expression by activated T cells is crucial to the resolution of immune responses through activation-induced cell death. 1 Besides activated T cells, FasL is expressed in immune-privileged sites, inducing apoptosis of self-reactive T cells infiltrating the site. 2 FasL expression by cancer cells has also been proposed to participate in tumor immune privilege. 3 Given the sensitivity of T cells to FasL-mediated apoptosis, it was hypothesized that enforced expression of FasL in allografts would create artificial immune privileged sites, allowing organ acceptance without having to resort to immunosuppressive drugs. 2 While enforced FasL expression prolonged allograft survival in certain models, several reports showed massive granulocyte infiltration leading to acute rejection. [4][5][6][7][8] The outcome of graft acceptance might depend on microenvironmental factors such as FasL expression levels, local cytokine expression, and cell types present near the graft site. In vitro migration assays have shown that FasL could behave as a neutrophil chemokine, 9,10 a claim disputed by others. 11,12 It is becoming increasingly clear that Fas engagement can mediate nonapoptotic signaling events, leading to cytokine and chemokine expression in different cell types. 13 For instance, serum-starved fibroblasts release interleukin 6 (IL-6) and IL-8 upon Fas engagement through transcription factor activation. 14 Caspase inhibition in Fas-treated T lymphocytes blocks apoptosis and unmasks proinflammatory cytokine release, also mediated through transcription factor activation. 15 Caspase activity has been reported to contribute to T-cell activation through selective caspase substrate cleavage in T cells without apoptosis. 16,17 Finally, naturally occurring caspase-8 mutations in humans not only prevents apoptosis but also leads to decreased T-lymphocyte activation. 18 Thus, Fas signaling and caspase activity can participate in T-cell activation and inflammatory processes.To better understand the contribution of FasL in neutrophil recruitment, in vitro migration assays were performed using cross-linked soluble FasL, since anti-Fas antibodies do not behave like the natural l...

Tumor-derived soluble MICs impair CD3+CD56+ NKT-like cell cytotoxicity in cancer patients

“…First, they lyze target cells in both MHC-restricted and non-MHC-restricted manners [39]. Second, FasL engagement cannot induce CD3 + CD56 + NKT apoptosis but rather triggers chemoattractant release [25]. Third, CD56 + NKT-like cells can induce CD56 − T cell activation and proliferation [40].…”

“…They both have the ability to kill NK-sensitive (U937) and NK-resistant (Raji) targets [25]. Given that CD3 + CD56 + cells kill targets using a mechanism similar to that used by CIKs, i.e., via NKG2D receptors [33], MIC expression in U937 and Raji cells and its role in NKG2D-mediated recognition and killing by CD3 + CD56 + cells were investigated.…”

“…Interestingly, these cells could mediate non-MHC-restricted as well as MHC-restricted lysis of malignant target cells and demonstrated strong antitumor activity in adoptive transfer experiments [27][28][29][30][31]. Studies indicated that CD3 + CD56 + NKT-like cells play an important role in cancer cell destruction by direct cell killing [25,27,31]. To our knowledge, data regarding the functional state of CD3 + CD56 + NKT-like cells in cancer patients is still lacking.…”

“…CD3 + CD56 + NKT-like cells are a minor population in the peripheral blood (<10%) and are abundant in the liver (up to 30%) [24]. A phenotypic study showed that the majority of NKT-like cells positively expressed CD8, CD28, and ␣␤TCR and were negative for V␣24 and CD1d tetramer staining [25,26]. Interestingly, these cells could mediate non-MHC-restricted as well as MHC-restricted lysis of malignant target cells and demonstrated strong antitumor activity in adoptive transfer experiments [27][28][29][30][31].…”

Decline in peripheral blood NKG2D+CD3+CD56+ NKT cells in metastatic colorectal cancer patients

“…Some experiments indicate that NKT cells generate antitumor activity in solid tumors and certain hematologic forms of cancer (7). Some of these reports suggest a protective role for iNKT and NKT-like cells compared to type II NKT cells showing to be majorly immunosuppressive (8,9). In general, iNKT cells were diminished signifi cantly in solid tumors, and the low frequencies of peripheral blood iNKT cells associate with poor prognosis in plenty of cancers (10)(11)(12).…”