Kidney double positive T cells have distinct characteristics in normal and diseased kidneys.
AKI
Cisplatin
DPT cells
Double positive T cells
Ischemia reperfusion
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
23 Feb 2024
23 Feb 2024
Historique:
received:
09
11
2023
accepted:
19
02
2024
medline:
24
2
2024
pubmed:
24
2
2024
entrez:
23
2
2024
Statut:
epublish
Résumé
Multiple types of T cells have been described and assigned pathophysiologic functions in the kidneys. However, the existence and functions of TCR+CD4+CD8+ (double positive; DP) T cells are understudied in normal and diseased murine and human kidneys. We studied kidney DPT cells in mice at baseline and after ischemia reperfusion (IR) and cisplatin injury. Additionally, effects of viral infection and gut microbiota were studied. Human kidneys from patients with renal cell carcinoma were evaluated. Our results demonstrate that DPT cells expressing CD4 and CD8 co-receptors constitute a minor T cell population in mouse kidneys. DPT cells had significant Ki67 and PD1 expression, effector/central memory phenotype, proinflammatory cytokine (IFNγ, TNFα and IL-17) and metabolic marker (GLUT1, HKII, CPT1a and pS6) expression at baseline. IR, cisplatin and viral infection elevated DPT cell proportions, and induced distinct functional and metabolic changes. scRNA-seq analysis showed increased expression of Klf2 and Ccr7 and enrichment of TNFα and oxidative phosphorylation related genes in DPT cells. DPT cells constituted a minor population in both normal and cancer portion of human kidneys. In conclusion, DPT cells constitute a small population of mouse and human kidney T cells with distinct inflammatory and metabolic profile at baseline and following kidney injury.
Identifiants
pubmed: 38396136
doi: 10.1038/s41598-024-54956-3
pii: 10.1038/s41598-024-54956-3
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4469Subventions
Organisme : NIDDK NIH HHS
ID : R01DK132278
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01DK123342
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01DK104662
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Rock, K. L., Latz, E., Ontiveros, F. & Kono, H. The sterile inflammatory response. Annu. Rev. Immunol. 28, 321–342. https://doi.org/10.1146/annurev-immunol-030409-101311 (2010).
doi: 10.1146/annurev-immunol-030409-101311
pubmed: 20307211
pmcid: 4315152
Shepherd, F. R. & McLaren, J. E. T cell immunity to bacterial pathogens: Mechanisms of immune control and bacterial evasion. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21176144 (2020).
doi: 10.3390/ijms21176144
pubmed: 32858901
pmcid: 7504484
Taylor, M. D., van der Werf, N. & Maizels, R. M. T cells in helminth infection: The regulators and the regulated. Trends Immunol. 33, 181–189. https://doi.org/10.1016/j.it.2012.01.001 (2012).
doi: 10.1016/j.it.2012.01.001
pubmed: 22398370
Walker, L. J., Sewell, A. K. & Klenerman, P. T cell sensitivity and the outcome of viral infection. Clin. Exp. Immunol. 159, 245–255. https://doi.org/10.1111/j.1365-2249.2009.04047.x (2010).
doi: 10.1111/j.1365-2249.2009.04047.x
pubmed: 19968665
pmcid: 2819491
Chopp, L., Redmond, C., O’Shea, J. J. & Schwartz, D. M. From thymus to tissues and tumors: A review of T-cell biology. J. Allergy Clin. Immunol. 151, 81–97. https://doi.org/10.1016/j.jaci.2022.10.011 (2023).
doi: 10.1016/j.jaci.2022.10.011
pubmed: 36272581
Lefaucheur, C. et al. T cell-mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts. Am. J. Transplant. 18, 377–390. https://doi.org/10.1111/ajt.14565 (2018).
doi: 10.1111/ajt.14565
pubmed: 29086461
Rampersad, C. et al. The negative impact of T cell-mediated rejection on renal allograft survival in the modern era. Am. J. Transplant. 22, 761–771. https://doi.org/10.1111/ajt.16883 (2022).
doi: 10.1111/ajt.16883
pubmed: 34717048
Stewart, B. J. et al. Spatiotemporal immune zonation of the human kidney. Science 365, 1461–1466. https://doi.org/10.1126/science.aat5031 (2019).
doi: 10.1126/science.aat5031
pubmed: 31604275
pmcid: 7343525
Singh, S. et al. Urinary T cells are detected in patients with immune checkpoint inhibitor-associated immune nephritis that are clonotypically identical to kidney T cell infiltrates. Oncoimmunology 11, 2124678. https://doi.org/10.1080/2162402X.2022.2124678 (2022).
doi: 10.1080/2162402X.2022.2124678
pubmed: 36185804
pmcid: 9519023
Krebs, C. F., Schmidt, T., Riedel, J. H. & Panzer, U. T helper type 17 cells in immune-mediated glomerular disease. Nat. Rev. Nephrol. 13, 647–659. https://doi.org/10.1038/nrneph.2017.112 (2017).
doi: 10.1038/nrneph.2017.112
pubmed: 28781371
Linke, A., Tiegs, G. & Neumann, K. Pathogenic T-cell responses in immune-mediated glomerulonephritis. Cells https://doi.org/10.3390/cells11101625 (2022).
doi: 10.3390/cells11101625
pubmed: 35626662
pmcid: 9139939
Rabb, H. et al. Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am. J. Physiol. Ren. Physiol. 279, F525-531. https://doi.org/10.1152/ajprenal.2000.279.3.F525 (2000).
doi: 10.1152/ajprenal.2000.279.3.F525
Liu, M. et al. A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity. J. Am. Soc. Nephrol. 17, 765–774. https://doi.org/10.1681/ASN.2005010102 (2006).
doi: 10.1681/ASN.2005010102
pubmed: 16481417
Bruggeman, L. A. Common mechanisms of viral injury to the kidney. Adv. Chronic Kidney Dis. 26, 164–170. https://doi.org/10.1053/j.ackd.2018.12.002 (2019).
doi: 10.1053/j.ackd.2018.12.002
pubmed: 31202388
pmcid: 6578596
Jang, H. R. et al. Early exposure to germs modifies kidney damage and inflammation after experimental ischemia-reperfusion injury. Am. J. Physiol. Ren. Physiol. 297, F1457-1465. https://doi.org/10.1152/ajprenal.90769.2008 (2009).
doi: 10.1152/ajprenal.90769.2008
Noel, S. et al. Gut microbiota-immune system interactions during acute kidney injury. Kidney360 2, 528–531. https://doi.org/10.34067/KID.0006792020 (2021).
doi: 10.34067/KID.0006792020
pubmed: 35369013
pmcid: 8785987
Ascon, D. B. et al. Normal mouse kidneys contain activated and CD3+CD4−CD8− double-negative T lymphocytes with a distinct TCR repertoire. J. Leukoc. Biol. 84, 1400–1409. https://doi.org/10.1189/jlb.0907651 (2008).
doi: 10.1189/jlb.0907651
pubmed: 18765477
pmcid: 2614602
Martina, M. N. et al. Double-negative alphabeta T cells are early responders to AKI and are found in human kidney. J. Am. Soc. Nephrol. 27, 1113–1123. https://doi.org/10.1681/ASN.2014121214 (2016).
doi: 10.1681/ASN.2014121214
pubmed: 26315532
Park, J. G. et al. Immune cell composition in normal human kidneys. Sci. Rep. 10, 15678. https://doi.org/10.1038/s41598-020-72821-x (2020).
doi: 10.1038/s41598-020-72821-x
pubmed: 32973321
pmcid: 7515917
Burne, M. J. et al. Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J. Clin. Invest. 108, 1283–1290. https://doi.org/10.1172/JCI12080 (2001).
doi: 10.1172/JCI12080
pubmed: 11696572
pmcid: 209434
Gandolfo, M. T. et al. Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int. 76, 717–729. https://doi.org/10.1038/ki.2009.259 (2009).
doi: 10.1038/ki.2009.259
pubmed: 19625990
Kinsey, G. R. et al. Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J. Am. Soc. Nephrol. 20, 1744–1753. https://doi.org/10.1681/ASN.2008111160 (2009).
doi: 10.1681/ASN.2008111160
pubmed: 19497969
pmcid: 2723989
Mehrotra, P. et al. Mutation of RORgammaT reveals a role for Th17 cells in both injury and recovery from renal ischemia-reperfusion injury. Am. J. Physiol. Ren. Physiol. 319, F796–F808. https://doi.org/10.1152/ajprenal.00187.2020 (2020).
doi: 10.1152/ajprenal.00187.2020
van der Putten, C. et al. CD8 and CD4 T cell populations in human kidneys. Cells https://doi.org/10.3390/cells10020288 (2021).
doi: 10.3390/cells10020288
pubmed: 33535505
pmcid: 7912772
Ordonez, L. et al. A higher risk of acute rejection of human kidney allografts can be predicted from the level of CD45RC expressed by the recipients’ CD8 T cells. PLoS One 8, e69791. https://doi.org/10.1371/journal.pone.0069791 (2013).
doi: 10.1371/journal.pone.0069791
pubmed: 23894540
pmcid: 3722168
Yap, M. et al. Expansion of highly differentiated cytotoxic terminally differentiated effector memory CD8+ T cells in a subset of clinically stable kidney transplant recipients: A potential marker for late graft dysfunction. J. Am. Soc. Nephrol. 25, 1856–1868. https://doi.org/10.1681/ASN.2013080848 (2014).
doi: 10.1681/ASN.2013080848
pubmed: 24652799
pmcid: 4116064
Li, H. et al. Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells. Nat. Commun. 11, 2859. https://doi.org/10.1038/s41467-020-16636-4 (2020).
doi: 10.1038/s41467-020-16636-4
pubmed: 32503973
pmcid: 7275084
Li, H. & Tsokos, G. C. Double-negative T cells in autoimmune diseases. Curr. Opin. Rheumatol. 33, 163–172. https://doi.org/10.1097/BOR.0000000000000778 (2021).
doi: 10.1097/BOR.0000000000000778
pubmed: 33394752
pmcid: 8018563
Bohner, P. et al. Double positive CD4(+)CD8(+) T cells are enriched in urological cancers and favor T Helper-2 polarization. Front. Immunol. 10, 622. https://doi.org/10.3389/fimmu.2019.00622 (2019).
doi: 10.3389/fimmu.2019.00622
pubmed: 30984190
pmcid: 6450069
Parel, Y. & Chizzolini, C. CD4+ CD8+ double positive (DP) T cells in health and disease. Autoimmun. Rev. 3, 215–220. https://doi.org/10.1016/j.autrev.2003.09.001 (2004).
doi: 10.1016/j.autrev.2003.09.001
pubmed: 15110234
Zhang, H. et al. Increased CD4(+)CD8(+) double positive t cells during Hantaan VIRUS INFECTION. Viruses https://doi.org/10.3390/v14102243 (2022).
doi: 10.3390/v14102243
pubmed: 36680178
pmcid: 9866815
Bocharov, G., Argilaguet, J. & Meyerhans, A. Understanding experimental LCMV infection of mice: The role of mathematical models. J. Immunol. Res. 2015, 739706. https://doi.org/10.1155/2015/739706 (2015).
doi: 10.1155/2015/739706
pubmed: 26576439
pmcid: 4631900
Gharaie, S. et al. Microbiome modulation after severe acute kidney injury accelerates functional recovery and decreases kidney fibrosis. Kidney Int. https://doi.org/10.1016/j.kint.2023.03.024 (2023).
doi: 10.1016/j.kint.2023.03.024
pubmed: 37011727
Noel, S. et al. Immune checkpoint molecule TIGIT regulates kidney T cell functions and contributes to AKI. J. Am. Soc. Nephrol. https://doi.org/10.1681/ASN.0000000000000063 (2023).
doi: 10.1681/ASN.0000000000000063
pubmed: 36747315
Bao, X., Qin, Y., Lu, L. & Zheng, M. Transcriptional regulation of early T-lymphocyte development in thymus. Front. Immunol. 13, 884569. https://doi.org/10.3389/fimmu.2022.884569 (2022).
doi: 10.3389/fimmu.2022.884569
pubmed: 35432347
pmcid: 9008359
Overgaard, N. H., Jung, J. W., Steptoe, R. J. & Wells, J. W. CD4+/CD8+ double-positive T cells: More than just a developmental stage?. J. Leukoc. Biol. 97, 31–38. https://doi.org/10.1189/jlb.1RU0814-382 (2015).
doi: 10.1189/jlb.1RU0814-382
pubmed: 25360000
Cheroutre, H. & Lambolez, F. Doubting the TCR coreceptor function of CD8alphaalpha. Immunity 28, 149–159. https://doi.org/10.1016/j.immuni.2008.01.005 (2008).
doi: 10.1016/j.immuni.2008.01.005
pubmed: 18275828
Clenet, M. L., Gagnon, F., Moratalla, A. C., Viel, E. C. & Arbour, N. Peripheral human CD4(+)CD8(+) T lymphocytes exhibit a memory phenotype and enhanced responses to IL-2, IL-7 and IL-15. Sci. Rep. 7, 11612. https://doi.org/10.1038/s41598-017-11926-2 (2017).
doi: 10.1038/s41598-017-11926-2
pubmed: 28912605
pmcid: 5599513
Quandt, D., Rothe, K., Scholz, R., Baerwald, C. W. & Wagner, U. Peripheral CD4CD8 double positive T cells with a distinct helper cytokine profile are increased in rheumatoid arthritis. PLoS One 9, e93293. https://doi.org/10.1371/journal.pone.0093293 (2014).
doi: 10.1371/journal.pone.0093293
pubmed: 24667579
pmcid: 3965555
Nguyen, P. et al. Expansion of CD4+CD8+ double-positive T cells in rheumatoid arthritis patients is associated with erosive disease. Rheumatology 61, 1282–1287. https://doi.org/10.1093/rheumatology/keab551 (2022).
doi: 10.1093/rheumatology/keab551
pubmed: 34260705
Macintyre, A. N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61–72. https://doi.org/10.1016/j.cmet.2014.05.004 (2014).
doi: 10.1016/j.cmet.2014.05.004
pubmed: 24930970
pmcid: 4079750
Michalek, R. D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303. https://doi.org/10.4049/jimmunol.1003613 (2011).
doi: 10.4049/jimmunol.1003613
pubmed: 21317389
Menard, L. C. et al. Renal cell carcinoma (RCC) tumors display large expansion of double positive (DP) CD4+CD8+ T cells with expression of exhaustion markers. Front. Immunol. 9, 2728. https://doi.org/10.3389/fimmu.2018.02728 (2018).
doi: 10.3389/fimmu.2018.02728
pubmed: 30534127
pmcid: 6275222
Sebzda, E., Zou, Z., Lee, J. S., Wang, T. & Kahn, M. L. Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat. Immunol. 9, 292–300. https://doi.org/10.1038/ni1565 (2008).
doi: 10.1038/ni1565
pubmed: 18246069
Choi, S. M., Park, H. J., Choi, E. A., Jung, K. C. & Lee, J. I. Cellular heterogeneity of circulating CD4(+)CD8(+) double-positive T cells characterized by single-cell RNA sequencing. Sci. Rep. 11, 23607. https://doi.org/10.1038/s41598-021-03013-4 (2021).
doi: 10.1038/s41598-021-03013-4
pubmed: 34880348
pmcid: 8655006
Percie du Sert, N. et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol. 18, e3000410. https://doi.org/10.1371/journal.pbio.3000410 (2020).
doi: 10.1371/journal.pbio.3000410
pubmed: 32663219
pmcid: 7360023
Ascon, D. B. et al. Phenotypic and functional characterization of kidney-infiltrating lymphocytes in renal ischemia reperfusion injury. J. Immunol. 177, 3380–3387. https://doi.org/10.4049/jimmunol.177.5.3380 (2006).
doi: 10.4049/jimmunol.177.5.3380
pubmed: 16920979