iNKT subsets differ in their developmental and functional requirements on Foxo1

Invariant natural killer T (iNKT) cells play important roles in regulating immune responses. Based on cytokine profiling and key transcriptional factors, iNKT cells are classified into iNKT1, iNKT2, and iNKT17 subsets. However, whether the development and functions of these subsets are controlled by distinct mechanisms remains unclear. Here, we show that forkhead box protein O1 (Foxo1) promotes differentiation of iNKT1 and iNKT2 cells but not iNKT17 cells because of its distinct contributions to IL7R expression in these subsets. Nuclear Foxo1 is essential for Il7r expression in iNKT1 and iNKT2 cells at early stages of differentiation but is dispensable in iNKT17 cells. RORγt, instead of Foxo1, promotes IL7R expression in iNKT17 cells. Additionally, Foxo1 is required for the effector function of iNKT1 and iNKT2 cells but not iNKT17 cells. Cytoplasmic Foxo1 promotes activation of mTORC1 in iNKT1 and iNKT2 cells through inhibiting TSC1–TSC2 interaction, whereas it is dispensable for mTORC1 activation in iNKT17 cells. iNKT17 cells display distinct metabolic gene expression patterns from iNKT1 and iNKT2 cells that match their different functional requirements on Foxo1. Together, our results demonstrate that iNKT cell subsets differ in their developmental and functional requirements on Foxo1.

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License to Kill: When iNKT Cells Are Granted the Use of Lethal Cytotoxicity

International Journal of Molecular Sciences ◽

10.3390/ijms21113909 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3909

Author(s):

Angélica Díaz-Basabe ◽

Francesco Strati ◽

Federica Facciotti

Keyword(s):

Immune Responses ◽

Inkt Cell ◽

Cell Cytotoxicity ◽

Future Perspectives ◽

Inkt Cells ◽

Cytotoxic Potential ◽

Lipid Antigens ◽

Cancer Immunotherapies ◽

Cluster Of Differentiation ◽

Invariant Natural Killer

Invariant Natural Killer T (iNKT) cells are a non-conventional, innate-like, T cell population that recognize lipid antigens presented by the cluster of differentiation (CD)1d molecule. Although iNKT cells are mostly known for mediating several immune responses due to their massive and diverse cytokine release, these cells also work as effectors in various contexts thanks to their cytotoxic potential. In this Review, we focused on iNKT cell cytotoxicity; we provide an overview of iNKT cell subsets, their activation cues, the mechanisms of iNKT cell cytotoxicity, the specific roles and outcomes of this activity in various contexts, and how iNKT killing functions are currently activated in cancer immunotherapies. Finally, we discuss the future perspectives for the better understanding and potential uses of iNKT cell killing functions in tumor immunosurveillance.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1521846113 ◽

2016 ◽

Vol 113 (27) ◽

pp. 7608-7613 ◽

Cited By ~ 12

Author(s):

Mohammad Nizam Uddin ◽

Dil Afroz Sultana ◽

Kyle J. Lorentsen ◽

Jonathan J. Cho ◽

Mariana E. Kirst ◽

...

Keyword(s):

T Cells ◽

Transcription Factor ◽

Immune Responses ◽

Cytokine Production ◽

Inkt Cells ◽

Double Positive ◽

Cell Numbers ◽

Function Identity ◽

Invariant Natural Killer

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.

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Different bacterial gene expression patterns and attenuated host immune responses are associated with the evolution of low-level vancomycin resistance during persistent methicillin-resistant Staphylococcus aureus bacteraemia

BMC Microbiology ◽

10.1186/1471-2180-8-39 ◽

2008 ◽

Vol 8 (1) ◽

pp. 39 ◽

Cited By ~ 77

Author(s):

Benjamin P Howden ◽

Danielle J Smith ◽

Ashley Mansell ◽

Paul DR Johnson ◽

Peter B Ward ◽

...

Keyword(s):

Gene Expression ◽

Staphylococcus Aureus ◽

Immune Responses ◽

Methicillin Resistant Staphylococcus Aureus ◽

Expression Patterns ◽

Gene Expression Patterns ◽

Bacterial Gene ◽

Methicillin Resistant ◽

Host Immune Responses ◽

Bacterial Gene Expression

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Cardiac physiology and metabolic gene expression during late organogenesis among F. heteroclitus embryo families from crosses between pollution-sensitive and -resistant parents

BMC Ecology and Evolution ◽

10.1186/s12862-022-01959-1 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Goran Bozinovic ◽

Zuying Feng ◽

Damian Shea ◽

Marjorie F. Oleksiak

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Expression Patterns ◽

Gene Expression Patterns ◽

Parental Effects ◽

Cardiac Physiology ◽

Heart Rates ◽

Metabolic Gene ◽

Metabolic Gene Expression ◽

Morphological Deformities

Abstract Background The teleost fish Fundulus heteroclitus inhabit estuaries heavily polluted with persistent and bioaccumulative chemicals. While embryos of parents from polluted sites are remarkably resistant to toxic sediment and develop normally, embryos of parents from relatively clean estuaries, when treated with polluted sediment extracts, are developmentally delayed, displaying deformities characteristic of pollution-induced embryotoxicity. To gain insight into parental effects on sensitive and resistant phenotypes during late organogenesis, we established sensitive, resistant, and crossed embryo families using five female and five male parents from relatively clean and predominantly PAH-polluted estuaries each, measured heart rates, and quantified individual embryo expression of 179 metabolic genes. Results Pollution-induced embryotoxicity manifested as morphological deformities, significant developmental delays, and altered cardiac physiology was evident among sensitive embryos resulting from crosses between females and males from relatively clean estuaries. Significantly different heart rates among several geographically unrelated populations of sensitive, resistant, and crossed embryo families during late organogenesis and pre-hatching suggest site-specific adaptive cardiac physiology phenotypes relative to pollution exposure. Metabolic gene expression patterns (32 genes, 17.9%, at p < 0.05; 11 genes, 6.1%, at p < 0.01) among the embryo families indicate maternal pollutant deposition in the eggs and parental effects on gene expression and metabolic alterations. Conclusion Heart rate differences among sensitive, resistant, and crossed embryos is a reliable phenotype for further explorations of adaptive mechanisms. While metabolic gene expression patterns among embryo families are suggestive of parental effects on several differentially expressed genes, a definitive adaptive signature and metabolic cost of resistant phenotypes is unclear and shows unexpected sensitive-resistant crossed embryo expression profiles. Our study highlights physiological and metabolic gene expression differences during a critical embryonic stage among pollution sensitive, resistant, and crossed embryo families, which may contribute to underlying resistance mechanisms observed in natural F. heteroclitus populations living in heavily contaminated estuaries.

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