Invariant Natural Killer T Cells Regulate Conventional Dendritic Cell Maturation to Re-establish Immune Tolerance to Rheumatoid Arthritis in DBA/1 Mice
-
Yaqi Wang
,
Min Zhang
,
Shengde Chen
,
Zheng Li
,
Ming Meng
Abstract
Rheumatoid arthritis (RA) is a type of autoimmune disease that results in immune disorder and excessive inflammatory response due to a reduction of self-tolerance. Invariant natural killer T (iNKT) cells can effectively alleviate clinical symptoms and hyper-inflammation in RA, but their mechanism of action is not well-defined. This study aims to investigate the mechanism of iNKT cell therapy for RA.
We established a DBA/1 mouse model for RA and treated it with specific iNKT cells. A cytometric bead array was used to measure the amounts of cytokines in the serum. Flow cytometry was then employed to identify different subsets of helper T cells (Th), the frequency of conventional dendritic cells (cDC), the expression of CD80, CD86, programmed cell death ligand 1 (PD-L1), and PD-L2 on cDC surfaces, and associated pathway proteins.
iNKT cell treatment reduced Th1/Th2 and Th17/ regulatory T (Treg) cell ratios while increasing interleukin-4 (IL-4) and IL-10. It enhanced the generation of immature cDCs, and it upregulated the level of PD-L2 by stimulating the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Meanwhile, it activated the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and inhibited the nuclear factor kappa B (NF-κB) pathway.
According to our findings, iNKT cell treatment increased the expression of phosphates STAT3 in lymph node cDC, causing them to upregulate PD-L2 molecules. While activating the ERK1/2 pathway and inhibiting the NF-κB pathway, tolerogenic cDC was produced, restoring immune homeostasis and correcting excessive inflammation. These results deliver new insights into the treatment of RA by iNKT cells.
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25. Chen D, Gao X, Wang J, Zhao H, Liu H, Chen S, et al. Activation of hepatic iNKT2 cells by alpha-GalCer ameliorates hepatic steatosis induced by high-fat diet in C57BL/6J mice. Int Immunopharmacol. 2019;74:105727.
26. Boisleve F, Kerdine-Romer S, Pallardy M. Implication of the MAPK pathways in the maturation of human dendritic cells induced by nickel and TNF-alpha. Toxicology. 2005;206(2):233-44.
27. Ade N, Antonios D, Kerdine-Romer S, Boisleve F, Rousset F, Pallardy M. NF-kappaB plays a major role in the maturation of human dendritic cells induced by NiSO(4) but not by DNCB. Toxicol Sci. 2007;99(2):488-501.
28. Mitsuo A, Morimoto S, Nakiri Y, Suzuki J, Kaneko H, Tokano Y, et al. Decreased CD161+CD8+ T cells in the peripheral blood of patients suffering from rheumatic diseases. Rheumatology (Oxford). 2006;45(12):1477-84.
29. Miellot A, Zhu R, Diem S, Boissier MC, Herbelin A, Bessis N. Activation of invariant NK T cells protects against experimental rheumatoid arthritis by an IL-10-dependent pathway. Eur J Immunol. 2005;35(12):3704-13.
30. Caielli S, Sorini C, Falcone M. The dangerous liaison between iNKT cells and dendritic cells: does it prevent or promote autoimmune diseases? Autoimmunity. 2011;44(1):11-22.
31. Zamani MR, Aslani S, Salmaninejad A, Javan MR, Rezaei N. PD-1/PD-L and autoimmunity: A growing relationship. Cell Immunol. 2016;310:27-41.
32. Nie X, Chen W, Zhu Y, Huang B, Yu W, Wu Z, et al. B7-DC (PD-L2) costimulation of CD4(+) T-helper 1 response via RGMb. Cell Mol Immunol. 2018;15(10):888-97.
33. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, et al. PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. Clin Cancer Res. 2017;23(12):3158-67.
34. Wolfle SJ, Strebovsky J, Bartz H, Sahr A, Arnold C, Kaiser C, et al. PD-L1 expression on tolerogenic APCs is controlled by STAT-3. Eur J Immunol. 2011;41(2):413-24.
2. Mousavi MJ, Karami J, Aslani S, Tahmasebi MN, Vaziri AS, Jamshidi A, et al. Transformation of fibroblast-like synoviocytes in rheumatoid arthritis; from a friend to foe. Auto Immun Highlights. 2021;12(1):3.
3. Liao KP. Cardiovascular disease in patients with rheumatoid arthritis. Trends Cardiovasc Med. 2017;27(2):136-40.
4. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205-19.
5. Kanashiro A, Shimizu Bassi G, de Queiroz Cunha F, Ulloa L. From neuroimunomodulation to bioelectronic treatment of rheumatoid arthritis. Bioelectron Med (Lond). 2018;1(2):151-65.
6. Hogquist K, Georgiev H. Recent advances in iNKT cell development. F1000Res. 2020;9.
7. Gapin L. Development of invariant natural killer T cells. Curr Opin Immunol. 2016;39:68-74.
8. Meng M, Liu H, Chen S, Zhao H, Gao X, Zhang J, et al. Methylation of H3K27 and H3K4 in key gene promoter regions of thymus in RA mice is involved in the abnormal development and differentiation of iNKT cells. Immunogenetics. 2019;71(7):489-99.
9. Giza HM, Bozzacco L. Unboxing dendritic cells: Tales of multi-faceted biology and function. Immunology. 2021;164(3):433-49.
10. Yin X, Chen S, Eisenbarth SC. Dendritic Cell Regulation of T Helper Cells. Annu Rev Immunol. 2021;39:759-90.
11. Iberg CA, Jones A, Hawiger D. Dendritic Cells As Inducers of Peripheral Tolerance. Trends Immunol. 2017;38(11):793-804.
12. Lutzky V, Hannawi S, Thomas R. Cells of the synovium in rheumatoid arthritis. Dendritic cells. Arthritis Res Ther. 2007;9(4):219.
13. Yu MB, Langridge WHR. The function of myeloid dendritic cells in rheumatoid arthritis. Rheumatol Int. 2017;37(7):1043-51.
14. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74-80.
15. Funes SC, Manrique de Lara A, Altamirano-Lagos MJ, Mackern-Oberti JP, Escobar-Vera J, Kalergis AM. Immune checkpoints and the regulation of tolerogenicity in dendritic cells: Implications for autoimmunity and immunotherapy. Autoimmun Rev. 2019;18(4):359-68.
16. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, et al. The nature of the principal type 1 interferon-producing cells in human blood. Science. 1999;284(5421):1835-7.
17. Anderson DA, 3rd, Murphy KM, Briseno CG. Development, Diversity, and Function of Dendritic Cells in Mouse and Human. Cold Spring Harb Perspect Biol. 2018;10(11).
18. Bochtler P, Kroger A, Schirmbeck R, Reimann J. Type I IFN-induced, NKT cell-mediated negative control of CD8 T cell priming by dendritic cells. J Immunol. 2008;181(3):1633-43.
19. Escriba-Garcia L, Alvarez-Fernandez C, Tellez-Gabriel M, Sierra J, Briones J. Dendritic cells combined with tumor cells and alpha-galactosylceramide induce a potent, therapeutic and NK-cell dependent antitumor immunity in B cell lymphoma. J Transl Med. 2017;15(1):115.
20. Sage PT, Schildberg FA, Sobel RA, Kuchroo VK, Freeman GJ, Sharpe AH. Dendritic Cell PD-L1 Limits Autoimmunity and Follicular T Cell Differentiation and Function. J Immunol. 2018;200(8):2592-602.
21. Caielli S, Conforti-Andreoni C, Di Pietro C, Usuelli V, Badami E, Malosio ML, et al. On/off TLR signaling decides proinflammatory or tolerogenic dendritic cell maturation upon CD1d-mediated interaction with invariant NKT cells. J Immunol. 2010;185(12):7317-29.
22. Meng M, Chen S, Gao X, Liu H, Wang Y, Zhang J, et al. Adoptive Immunotherapy of iNKT Cells in Glucose-6-Phosphate Isomerase (G6PI)-Induced RA Mice. J Vis Exp. 2020(155).
23. Chen D, Liu H, Wang Y, Chen S, Liu J, Li W, et al. Study of the adoptive immunotherapy on rheumatoid arthritis with Thymus-derived invariant natural killer T cells. Int Immunopharmacol. 2019;67:427-40.
24. Chen D, Xu W, Teng J, Liu H, Wang Y, Wang Y, et al. Migration, Distribution, and Safety Evaluation of Specific Phenotypic and Functional Mouse Spleen-Derived Invariant Natural Killer T2 Cells after Adoptive Infusion. Mediators Inflamm. 2021;2021:5170123.
25. Chen D, Gao X, Wang J, Zhao H, Liu H, Chen S, et al. Activation of hepatic iNKT2 cells by alpha-GalCer ameliorates hepatic steatosis induced by high-fat diet in C57BL/6J mice. Int Immunopharmacol. 2019;74:105727.
26. Boisleve F, Kerdine-Romer S, Pallardy M. Implication of the MAPK pathways in the maturation of human dendritic cells induced by nickel and TNF-alpha. Toxicology. 2005;206(2):233-44.
27. Ade N, Antonios D, Kerdine-Romer S, Boisleve F, Rousset F, Pallardy M. NF-kappaB plays a major role in the maturation of human dendritic cells induced by NiSO(4) but not by DNCB. Toxicol Sci. 2007;99(2):488-501.
28. Mitsuo A, Morimoto S, Nakiri Y, Suzuki J, Kaneko H, Tokano Y, et al. Decreased CD161+CD8+ T cells in the peripheral blood of patients suffering from rheumatic diseases. Rheumatology (Oxford). 2006;45(12):1477-84.
29. Miellot A, Zhu R, Diem S, Boissier MC, Herbelin A, Bessis N. Activation of invariant NK T cells protects against experimental rheumatoid arthritis by an IL-10-dependent pathway. Eur J Immunol. 2005;35(12):3704-13.
30. Caielli S, Sorini C, Falcone M. The dangerous liaison between iNKT cells and dendritic cells: does it prevent or promote autoimmune diseases? Autoimmunity. 2011;44(1):11-22.
31. Zamani MR, Aslani S, Salmaninejad A, Javan MR, Rezaei N. PD-1/PD-L and autoimmunity: A growing relationship. Cell Immunol. 2016;310:27-41.
32. Nie X, Chen W, Zhu Y, Huang B, Yu W, Wu Z, et al. B7-DC (PD-L2) costimulation of CD4(+) T-helper 1 response via RGMb. Cell Mol Immunol. 2018;15(10):888-97.
33. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, et al. PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. Clin Cancer Res. 2017;23(12):3158-67.
34. Wolfle SJ, Strebovsky J, Bartz H, Sahr A, Arnold C, Kaiser C, et al. PD-L1 expression on tolerogenic APCs is controlled by STAT-3. Eur J Immunol. 2011;41(2):413-24.
| Files | ||
| Issue | Vol 23 No 3 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v23i3.15639 | |
| Keywords | ||
| Dendritic cells Extracellular signal-regulated kinase Invariant natural killer T cells Nuclear factor kappa B Rheumatoid arthritis | ||
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How to Cite
1.
Wang Y, Zhang M, Chen S, Li Z, Meng M. Invariant Natural Killer T Cells Regulate Conventional Dendritic Cell Maturation to Re-establish Immune Tolerance to Rheumatoid Arthritis in DBA/1 Mice. Iran J Allergy Asthma Immunol. 2024;23(3):299-310.
