CD1d-unrestricted NKT cells are endowed with a hybrid function far superior than that of iNKT cells

Farr, Alexander R.; Wu, Weisheng; Choi, Bomi; Cavalcoli, James D.; Laouar, Yasmina

doi:10.1073/pnas.1323405111

Cited by 15 publications

(21 citation statements)

References 47 publications

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“…Both Nkp46 and Gzmb were very modestly expressed in the wild-type thymic and splenic iNKT cells at steady state (Fig. 6), similar to what has been recently reported (43). Removal of Bcl11b resulted in the up-regulation of Nkp46 and Gzmb in all of the three effector subsets both in thymus and spleen (Fig.…”

Section: Bcl11b Restricts Expression Of Inkt17 Program In Inkt1 and Isupporting

confidence: 84%

Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival

Uddin

Sultana

Lorentsen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Invariant natural killer T (iNKT) cells are innate-like T cells that recognize glycolipid antigens and play critical roles in regulation of immune responses. Based on expression of the transcription factors (TFs) Tbet, Plzf, and Rorγt, iNKT cells have been classified in effector subsets that emerge in the thymus, namely, iNKT1, iNKT2, and iNKT17. Deficiency in the TF Bcl11b in double-positive (DP) thymocytes has been shown to cause absence of iNKT cells in the thymus and periphery due to defective self glycolipid processing and presentation by DP thymocytes and undefined intrinsic alterations in iNKT precursors. We used a model of cre-mediated postselection deletion of Bcl11b in iNKT cells to determine its intrinsic role in these cells. We found that Bcl11b is expressed equivalently in all three effector iNKT subsets, and its removal caused a reduction in the numbers of iNKT1 and iNKT2 cells, but not in the numbers of iNKT17 cells. Additionally, we show that Bcl11b sustains subset-specific cytokine production by iNKT1 and iNKT2 cells and restricts expression of iNKT17 genes in iNKT1 and iNKT2 subsets, overall restraining the iNKT17 program in iNKT cells. The total numbers of iNKT cells were reduced in the absence of Bcl11b both in the thymus and periphery, associated with the decrease in iNKT1 and iNKT2 cell numbers and decrease in survival, related to changes in survival/apoptosis genes. Thus, these results extend our understanding of the role of Bcl11b in iNKT cells beyond their selection and demonstrate that Bcl11b is a key regulator of iNKT effector subsets, their function, identity, and survival.iNKT cell program | transcription factor Bcl11b | iNKT1 effector cells | iNKT2 effector cells | iNKT17 effector cells

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Section: Bcl11b Restricts Expression Of Inkt17 Program In Inkt1 and Isupporting

confidence: 84%

Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival

Uddin

Sultana

Lorentsen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, a recent study reported that vectors expressing the NKG2D ligand RAE-1γ dramatically enhanced the effectiveness of CD8 + T-cell response suggesting a promising approach in the development of CD8 + T-cell–based vaccines (41). Accordingly, one possible candidate for the origin of innate CD8 + NKT cell function is the subset of MHC-unrestricted NKT cells (42, 43). These NKT cells have been recently described as sharing many characteristics of NK cells including the expression of the killer cell lectin-like receptors (Klr), the rapid production of IFNγ in response to cytokine stimuli (IL-12/IL-18), and the potent cytotoxic program (granzyme B) in response to innate signals (Poly:IC) (43).…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, one possible candidate for the origin of innate CD8 + NKT cell function is the subset of MHC-unrestricted NKT cells (42, 43). These NKT cells have been recently described as sharing many characteristics of NK cells including the expression of the killer cell lectin-like receptors (Klr), the rapid production of IFNγ in response to cytokine stimuli (IL-12/IL-18), and the potent cytotoxic program (granzyme B) in response to innate signals (Poly:IC) (43). Notably, the identity of these T cells as MHC-unrestricted T cells makes them excellent candidates to serve as professional innate T cells while maintaining adaptive functions.…”

Section: Discussionmentioning

confidence: 99%

Dissecting CD8+ NKT Cell Responses to Listeria Infection Reveals a Component of Innate Resistance

Seregin

Chen

Laouar

2015

The Journal of Immunology

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A small pool of NK1.1+ CD8+ T cells is harbored among the “conventional” CD8+ T cell compartment. Conclusions driven from analysis of immune responses mediated by cytotoxic CD8+ T cells are often made on the total population, which includes these “contaminating” NK1.1+ CD8+ T cells. An as yet unresolved question is whether NK1.1+ CD8+ cells are conventional T cells that acquire NK1.1 expression upon activation or delineation into memory phenotype, or whether they are a distinct cell population that induces immune responses in a different manner than conventional T cells. To address this question, we used the Listeria monocytogenes model of infection and followed CD8+ NK1.1+ T cells alongside NK1.1− CD8+ T cells in each phase of the immune response: innate, effector and memory. Our central finding is that CD8+ NK1.1+ cells and conventional NK1.1− CD8+ T cells both contribute to the adaptive immune response to Listeria, but only CD8+ NK1.1+ cells were equipped with the ability to provide a rapid innate immune response, as demonstrated by early and antigen-independent IFNγ production, granzyme B expression, and degranulation. More importantly, purified conventional CD8+ T cells alone in the absence of any “contaminating” CD8+ NK1.1+ cells were not sufficient to provide early protection to lethally infected mice. These results highlight the role of CD8+ NK1.1+ T cells in mounting early innate responses important for host defense and support the therapeutic potential of this subset to improve the effectiveness of protective immunity.

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“…They constitute a subset of T lymphocytes that express some natural killer cell receptors. However, they are not restricted by CD1d molecules, so they are also called CD1d independent NKT (CD1d ind NKT) [ 35 ]. Scientists have confirmed a highly specialised effector-memory phenotype of these lymphocytes, thus their percentage in peripheral blood increases with age.…”

Section: Subsets Of Natural Killer T-cellsmentioning

confidence: 99%

A brief review of clinical trials involving manipulation of invariant NKT cells as a promising approach in future cancer therapies

Waldowska

Bojarska‐Junak

Roliński

2017

cejoi

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In the recent years researchers have put a lot of emphasis on the possible immunotherapeutic strategies able to target tumors. Many studies have proven that the key role in recognition and eradication of cancer cells, both for mice and humans, is being conducted by the invariant natural killer T-cells (NKT). This small subpopulation of lymphocytes can kill other cells, either directly or indirectly, through the natural killer cells’ (NK) activation. They can also swiftly release cytokines, causing the involvement of elements of the innate and acquired immune system. With the discovery of α-galactosylceramide (α-GalCer) – the first known agonist for iNKT cells – and its later subsequent analogs, it became possible to effectively stimulate iNKT cells, hence to keep control over the tumor progression. This article refers to the current knowledge concerning iNKT cells and the most important aspects of their antitumor activity. It also highlights the clinical trials that aim at increasing the amount of iNKT cells in general and in the microenvironment of the tumor. For sure, the iNKT-based immunotherapeutic approach holds a great potential and is highly probable to become a part of the cancer immunotherapy in the future.

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CD1d-unrestricted NKT cells are endowed with a hybrid function far superior than that of iNKT cells

Cited by 15 publications

References 47 publications

Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival

Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival

Dissecting CD8+ NKT Cell Responses to Listeria Infection Reveals a Component of Innate Resistance

A brief review of clinical trials involving manipulation of invariant NKT cells as a promising approach in future cancer therapies

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