Endothelial MHC-I-peptides specificity in IFN-gamma induced cytoprotection against natural killing

Invariant NKT (iNKT) cells have been shown to be pro-inflammatory or anti-inflammatory in many pathologic conditions including infections, cancer, autoimmune diseases and allergy. Additionally, early expansion of iNKT cells correlates with successful engraftment and low incidence of graft-versus host disease suggesting a role for iNKT cells in tolerance to allogeneic transplantation. iNKT cells recognize glycolipids bound to CD1d via their T cell receptor (TCR), but also express the inhibitory receptors for MHC class I ligands (MHC I.) Little is known regarding the importance of iNKT cell self-recognition of MHC I during development and the occurrence of autoimmunity, allergy or tolerance to in utero hematopoietic cellular transplantation (IUHCT). Given the importance of NK cell self-recognition during development, we hypothesized that, like NK cells, self-engagement of MHC I inhibitory receptors during development alters the phenotype and function of self-responsive iNKT cells. Prenatal allogeneic chimeras were established by in utero transplantation of Balb/c fetal liver light density cells at E14 into age-matched C57BL/6 fetal recipients. A kinetic evaluation of iNKT cell receptor expression and function was performed after birth. iNKT cells were evaluated for expression of activating (Ly49D) and inhibitory (Ly49A, F, G) receptors specific for the donor MHC I (H-2d.) The functional response of iNKT cell subsets was measured following in vivo activation with KRN7000, the ligand for iNKT cells. Intracellular cytokine production (IFN-gamma and IL-4) production was assessed in the alloresponsive Ly49A+ iNKT cell subset and compared to naïve controls and B10.D2 (H2d) mice. We found that a negligible fraction of iNKT cells expressed the activating Ly49D receptor in either chimera or controls (<1%.) In chimeric mice, the frequency of iNKT cells expressing Ly49A, F, or G did not change significantly. However, the levels of Ly49A expression were significantly reduced on iNKT cells from all organs tested suggesting developmental recognition of donor class I ligands had occurred. These reduced receptor levels did not appear to be due to sequestration as acid stripping did not alter the phenotype. Lastly, Ly49A+ but not Ly49A- iNKT cells in chimeric mice exhibited significantly increased production of IL-4 in response to TCR stimulation suggesting a shift toward a regulatory phenotype. Consistent with this finding, IFN-gamma levels in chimeras were minimally changed compared to controls. These findings indicate that inhibitory receptor self-engagement during development leads to: 1) alterations in receptor expression; 2) shift toward a tolerogenic phenotype in self-responsive iNKT cell phenotypes; and 3) no change in the receptor expression or function of non-responsive iNKT cell phenotypes. Further studies will directly evaluate the impact of self-recognition of iNKT cells in the pathogenesis of autoimmunity and allergy or tolerance following IUHCT. Disclosures: No relevant conflicts of interest to declare.

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Decreased MHC I expression in IFN gamma mutant mice alters synaptic elimination in the spinal cord after peripheral injury

Journal of Neuroinflammation ◽

10.1186/1742-2094-9-88 ◽

2012 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

Sheila CS Victório ◽

Luciana P Cartarozzi ◽

Rafaela CR Hell ◽

Alexandre LR Oliveira

Keyword(s):

Spinal Cord ◽

Mutant Mice ◽

Ifn Gamma ◽

Mhc I ◽

Peripheral Injury

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Serum interferon-gamma (IFN-gamma) in chronic oral candidosis

Medical Mycology ◽

10.1046/j.1365-280x.1998.00157.x ◽

1998 ◽

Vol 36 (5) ◽

pp. 269-273

Author(s):

SZKARADKIEWICZ ◽

SZPONAR ◽

KRZEMINSKA-JASKOWIAK ◽

TUECKA

Keyword(s):

Interferon Gamma ◽

Ifn Gamma ◽

Oral Candidosis

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Author response for "TNF‐alpha and IL‐1beta sensitize human MSC for IFN‐gamma signalling and enhance neutrophil recruitment"

10.1002/eji.201948336/v3/response1 ◽

2020 ◽

Author(s):

Alexander Hackel ◽

Aleksandra Aksamit ◽

Kirsten Bruderek ◽

Stephan Lang ◽

Sven Brandau

Keyword(s):

Neutrophil Recruitment ◽

Author Response ◽

Tnf Alpha ◽

Ifn Gamma

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Decision letter for "TNF‐alpha and IL‐1beta sensitize human MSC for IFN‐gamma signalling and enhance neutrophil recruitment"

10.1002/eji.201948336/v1/decision1 ◽

2019 ◽

Keyword(s):

Neutrophil Recruitment ◽

Tnf Alpha ◽

Ifn Gamma

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Effects of Retinoic Acid and 1,25-Dihydroxyvitamin D3 on IFN-gamma Secretion by Mononuclear Leukocytes from Nulliparous and Postparturient Dairy Cattle

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.70.3.92 ◽

2000 ◽

Vol 70 (3) ◽

pp. 92-101 ◽

Cited By ~ 14

Author(s):

Burim Ametaj ◽

Brian Nonnecke ◽

Ronald Horst ◽

Donald Beitz

Keyword(s):

Retinoic Acid ◽

Dairy Cattle ◽

Dairy Cows ◽

Dairy Cow ◽

Pokeweed Mitogen ◽

Mononuclear Leukocytes ◽

Combined Effects ◽

Ifn Gamma ◽

Dihydroxyvitamin D ◽

1,25 Dihydroxyvitamin D

Individual and combined effects of several isomers of retinoic acid (RA) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on interferon-gamma (IFN-gamma) secretion by blood mononuclear leukocytes (MNL) from nulliparous and postparturient Holstein cattle were evaluated in vitro. In the first experiment, effects on incubation period (24 to 72 hours) and time of supplementation (0 to 32 hours) with all-trans, 9-cis, 13-cis-, and 9,13-dicis-RAs (0 to 100 nM) on IFN-gamma secretion by pokeweed mitogen (PWM)-stimulated (0 and 10 mug/ml) MNL from nulliparous cattle were evaluated. In the second experiment, MNL from postparturient cows (bled at 0, 2, 4, and 16 days postpartum) were stimulated with PWM (0 and 10 mug/ml) in the presence of RA isomers (9-cis- or 9,13-dicis-RA; 0 to 100 nM), 1,25-(OH)2D3 (0 to 100 nM), or with combinations of these metabolites. The results show that individual isomers of RA had no effect on IFN-gamma secretion by PWM-stimulated MNL from nulliparous or postparturient cows. Furthermore 1,25-dihydroxyvitamin D3 inhibited IFN-gamma secretion by MNL from nulliparous and postparturient dairy cows; however, the degree of inhibition was greater when 9-cis- and 9,13-dicis-RA were also present in the cultures. Finally mononuclear leukocytes from postparturient dairy cows produced substantially less IFN-gamma than did MNL from nulliparous cattle. It is concluded that retinoic acids individually did not affect the capacity of leukocytes from dairy cattle to secrete IFN-gamma. This result is in marked contrast to studies in monogastric species indicating that RAs inhibit IFN-gamma secretion by peripheral blood T cells. Inhibition of IFN-gamma secretion by 1,25-(OH)2D3 was potentiated by 9-cis- and 9,13-di-cis-retinoics acids, suggesting that an excess of dietary vitamins A and D may compromise further the naturally immunosuppressed postparturient dairy cow. Additional research is necessary to determine if the combined effects of these metabolites on IFN-gamma secretion represent an increased susceptibility of the dairy cow to infectious diseases during the periparturient period. Lower secretion of IFN-gamma by MNL from postpartutient dairy cows, relative to nulliparous cattle, suggests that recently-calved cows are naturally immunosuppressed.

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Effects of Increased Dietary Protein and Energy on Composition and Functional Capacities of Blood Mononuclear Cells from Vaccinated, Neonatal Calves

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.75.5.357 ◽

2005 ◽

Vol 75 (5) ◽

pp. 357-368 ◽

Cited By ~ 8

Author(s):

Foote ◽

Nonnecke† ◽

Waters ◽

Palmer ◽

Beitz ◽

...

Keyword(s):

Weight Gain ◽

B Cell ◽

Dietary Protein ◽

Crude Protein ◽

Interleukin 2 ◽

Milk Replacer ◽

Standard Diet ◽

Gamma Delta ◽

Ifn Gamma ◽

Functional Capacities

Effects of increased protein and energy provided by an intensified milk replacer on the antigen-specific, cell-mediated immune response of the neonatal calf were examined. Calves were fed a standard (0.45 kg/day of a 20% crude protein, 20% fat milk replacer; n = 11) or intensified (1.14 kg/day of a 28% crude protein, 20% fat milk replacer; n = 11) diet from 0 to 6 weeks of age. All calves were vaccinated with Mycobacterium bovis bacillus Calmette-Guerin (BCG) at 1 week of age. The daily weight gain of intensified-diet calves (0.62 kg/day) was greater than the weight gain of standard-diet calves (0.29 kg/day). Liver, kidney, heart, thymus, and subcervical lymph nodes from intensified-diet calves were heavier than the same organs from standard-diet calves. Flow cytometric analysis of peripheral blood mononuclear cell (PBMC) populations indicated that CD4+ cells, gamma delta TCR+ cells, and monocyte percentages, although unaffected by diet during the first 5 weeks of the study, were higher in intensified-diet calves at week 6. The decline in gamma deltad TCR+ cell percentages and increase in B cell percentages with increasing age seen in all calves are characteristic of the maturing immune system of the calf. CD8+ T cell or B cell percentages were not affected by diet. In intensified-diet calves, percentages of CD4+ expressing interleukin-2 receptor increased and percentages of gamma delta TCR+ cells expressing interleukin-2 receptor decreased with time. The same populations in standard-diet calves did not change with time. Percentages of CD4+ and CD8+ T cells, and B cells expressing MHC class II antigen, were unaffected by diet or age. Although mitogen-induced interferon (IFN)-gamma and nitric oxide (NO) secretion increased with age for all calves, PBMC from intensified-diet calves produced less IFN-gamma and more NO than did cells from standard-diet calves at week 6 of the study. Antigen-induced secretion of IFN-gamma and NO also increased with age but was unaffected by diet. Antigen-elicited delayed-type hypersensitivity was unaffected by diet, suggesting increased dietary protein and energy did not alter adaptive immunity in vivo. Overall, these results suggest that feeding calves a commercially available, intensified milk replacer affects minimally the composition and functional capacities of PBMC populations. Additional research is necessary to determine whether these subtle effects influence the calf’s susceptibility to infectious disease.

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