Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-γ production by invariant natural killer T cells

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2415-2420 ◽  
Author(s):  
Pierre Gourdy ◽  
Luiza M. Araujo ◽  
Ren Zhu ◽  
Barbara Garmy-Susini ◽  
Séverine Diem ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Interleukin 4 ◽  
Response To Treatment ◽  
Inkt Cells ◽  
Gender Dimorphism ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Mechanisms accounting for gender dimorphism during immune responses are still poorly understood. Since invariant natural killer T (iNKT) cells exert important regulatory functions through their capacity to produce both T helper 1 (Th1) and Th2 cytokines, we addressed the question of whether these activities could be modulated by sexual hormones. We found that in vivo challenge with the specific ligand of iNKT cells, α-galactosylceramide (α-GalCer), induced significantly higher concentrations of interferon γ (IFN-γ) in the serum of female than in that of male mice, while interleukin 4 (IL-4) production was not modified. In support of a crucial role of ovarian hormones in this phenomenon, a significant decrease of serum IFN-γ concentrations occurred in ovariectomized females, in response to treatment with α-GalCer, while orchidectomy affected neither IFN-γ nor IL-4 serum concentrations in males. The implication of estrogens in this selective enhancement of IFN-γ production by iNKT cells was demonstrated by (1) the increased α-GalCer–induced IFN-γ synthesis by iNKT cells upon both in vitro and in vivo exposure to estradiol and (2) the abolition of the sex-linked difference in α-GalCer–induced IFN-γ release in estrogen receptor α-deficient mice. These results provide the first evidence that estrogens influence iNKT cells leading to this gender dimorphism in their cytokine production profile.

scholarly journals Combination of NKT14m and Low Dose IL-12 Promotes Invariant Natural Killer T Cell IFN-γ Production and Tumor Control

2020 ◽  
Vol 21 (14) ◽  
pp. 5085
Author(s):  
Peng Guan ◽  
Robert Schaub ◽  
Kim E. Nichols ◽  
Rupali Das
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Low Dose ◽  
Inkt Cell ◽  
Tumor Control ◽  
Inkt Cells ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d+ tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions.

scholarly journals Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases

2020 ◽  
Vol 34 (2) ◽  
pp. e00232-20
Author(s):  
Nicolás M. S. Gálvez ◽  
Karen Bohmwald ◽  
Gaspar A. Pacheco ◽  
Catalina A. Andrade ◽  
Leandro J. Carreño ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Infectious Diseases ◽  
Natural Killer ◽  
Nkt Cells ◽  
Interleukin 4 ◽  
Type I ◽  
Inkt Cells ◽  
Class I Mhc ◽  
Natural Killer T

SUMMARYThe immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.

scholarly journals Vaccine Based on Dendritic Cells Electroporated with an Exogenous Ovalbumin Protein and Pulsed with Invariant Natural Killer T Cell Ligands Effectively Induces Antigen-Specific Antitumor Immunity

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 171
Author(s):  
Akihiro Watanabe ◽  
Kimihiro Yamashita ◽  
Mitsugu Fujita ◽  
Akira Arimoto ◽  
Masayasu Nishi ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Natural Killer ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Tumor Antigens ◽  
Vaccine Strategy ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

(1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells.

Distinct homeostatic requirements of CD4+ and CD4- subsets of Vα24-invariant natural killer T cells in humans

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4150-4156 ◽  
Author(s):  
Denis V. Baev ◽  
Xiao-hui Peng ◽  
Liping Song ◽  
Jerry R. Barnhart ◽  
Gay M. Crooks ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Natural Killer T Cells ◽  
Cd4 Cells ◽  
Functional Maturation ◽  
Killer T Cells ◽  
Invariant Natural Killer ◽  
Peripheral Expansion ◽  
Natural Killer T

Abstract CD1d-restricted Vα24-invariant natural killer T cells (iNKTs) are important in immunoregulation. CD4+ and CD4- iNKTs develop with similar frequencies in murine thymus and depend on interleukin-15 (IL-15) in periphery. However, homeostatic requirements of iNKTs have not been analyzed in humans. We evaluated thymic production, peripheral dynamics, and functional maturation of human iNKTs. CD4+ subset comprises 90% of iNKTs in mature thymocytes and cord blood (CB) but only 40% in adult blood. Using T-cell receptor excision circle (TREC) analysis, we directly measured in vivo replicative history of CD4+ and CD4- iNKT cells. Compared to CD4+, CD4- iNKTs contain fewer TRECs, express higher levels of IL-2Rβ, and proliferate with higher rate in response to IL-15. In contrast, CD4+ cells express higher levels of IL-7Rα and better respond to IL-7. Neither thymic nor CB iNKTs are able to produce cytokines unless they are induced to proliferate. Therefore, unlike in the mouse, human CD4+ iNKTs are mainly supported by thymic output and limited peripheral expansion, whereas CD4- cells undergo extensive peripheral expansion, and both subsets develop their functions in periphery. These findings reveal important differences in homeostatic requirements and functional maturation between murine and human iNKTs that are to be considered for clinical purposes.

scholarly journals Activation of invariant natural killer T cells impedes liver regeneration by way of both IFN-γ- and IL-4-dependent mechanisms

Hepatology ◽  
2014 ◽  
Vol 60 (4) ◽  
pp. 1356-1366 ◽  
Author(s):  
Shi Yin ◽  
Hua Wang ◽  
Adeline Bertola ◽  
Dechun Feng ◽  
Ming-jiang Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Liver Regeneration ◽  
Natural Killer ◽  
Natural Killer T Cells ◽  
Ifn Γ ◽  
Killer T Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

Efficient Regeneration of Human Vα24+Invariant Natural Killer T Cells and Their Anti-Tumor Activity In Vivo

Stem Cells ◽  
2016 ◽  
Vol 34 (12) ◽  
pp. 2852-2860 ◽  
Author(s):  
Daisuke Yamada ◽  
Tomonori Iyoda ◽  
Raul Vizcardo ◽  
Kanako Shimizu ◽  
Yusuke Sato ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Natural Killer T Cells ◽  
Efficient Regeneration ◽  
Anti Tumor Activity ◽  
Killer T Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

scholarly journals In vivo activation of invariant natural killer T cells induces systemic and local alterations in T-cell subsets prior to preterm birth

2017 ◽  
Vol 189 (2) ◽  
pp. 211-225 ◽  
Author(s):  
N. Gomez-Lopez ◽  
R. Romero ◽  
M. Arenas-Hernandez ◽  
G. Schwenkel ◽  
D. St Louis ◽  
...  
Keyword(s):  
T Cells ◽  
Preterm Birth ◽  
T Cell ◽  
Natural Killer ◽  
Natural Killer T Cells ◽  
T Cell Subsets ◽  
Killer T Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

scholarly journals Human invariant natural killer T cells promote tolerance by preferential apoptosis induction of conventional dendritic cells

Haematologica ◽  
2021 ◽  
Author(s):  
Hannes Schmid ◽  
Emmanuelle M. Ribeiro ◽  
Kathy-Ann Secker ◽  
Silke Duerr-Stoerzer ◽  
Hildegard Keppeler ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inkt Cells ◽  
Healthy Donors ◽  
Invariant Natural Killer ◽  
Natural Killer T

Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. We recently showed in murine studies and in vitro human models that adoptively transferred invariant natural killer T (iNKT) cells protect from GvHD and promote graft-versus-leukemia effects. The cellular mechanisms underlying GvHD prevention by iNKT cells in humans, however, remain unknown. To study relevant cellular interactions, dendritic cells (DCs) were either generated from monocytes or isolated directly from blood of healthy donors or GvHD patients and co-cultured in a mixed lymphocyte reaction (MLR) with T cells obtained from healthy donors or transplantation bags. Addition of culture-expanded iNKT cells to the MLR induced DC apoptosis in a cell contact-dependent manner, thereby preventing T-cell activation and proliferation. Annexin V/PI staining and image stream assays showed that CD4+CD8-, CD4-CD8+ and double negative iNKT cells are similarly able to induce DC apoptosis. Further MLR assays revealed that conventional DCs (cDCs) but not plasmacytoid DCs (pDCs) could induce alloreactive T-cell activation and proliferation. Interestingly, cDCs were also more susceptible to apoptosis induced by iNKT cells, which correlates with their higher CD1d expression, leading to a bias in favor of pDCs. Remarkably, these results could also be observed in GvHD patients. We propose a new mechanism how ex vivo expanded human iNKT cells prevent alloreactivity of T cells. iNKT cells modulate T-cell responses by selective apoptosis of DC subsets, resulting in suppression of T-cell activation and proliferation while enabling beneficial immune responses through pDCs.

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