Main circulating CD8⁺ T cell subsets in patients with systemic lupus erythematosus

Relevance. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and sustained production of autoantibodies.
The aim of the study – to compare composition of peripheral blood cytotoxic CD8⁺ T lymphocytes (Tc) subsets and assess the clinical significance of them in systemic lupus erythematosus. Materials and methods. A total of 35 SLE patients and 49 healthy volunteers were included in the study. Phenotyping of peripheral blood T cell subpopulations was carried out by means of flow cytometry. T lymphocytes were determined using CD3⁺, CD4⁺, CD8⁺ antibodies. Tc were identified by using CD45RA and CD62L antibodies. Also the expression of chemokine receptors (CCR4, CCR6, CXCR3 and CXCR5) on Tc cells was assessed and the main Tc subpopulations were determined: Type 1 (Tc1), type 2 (Tc2), type 17 (Tc17), type 17/1 (Tc17.1), type 17/22 (Tc17.22) cytotoxic cells and T follicular cytotoxic cells (Tfc).
Results. The absolute and relative number of Tc was significantly higher in the group of patients with SLE compared with the control group. Additionally, there was a significant decrease in the relative number of Tc1, Tc 17.1 and Tfc1 and a significant increase in the relative number of Tc2, Tfc 17 and Tfc17.1 within the SLE group when compared to the control group. There were significant positive correlationfor Tc1 and levels of C3 and C4 complement components (r=0.404, p<0.05).
Conclusions. The absolute and relative number of peripheral blood Tc subsets is altered in SLE patients compared with the control group. It was found that patients with SLE contained increased number of Tc2 cells, which seems to be associated with markers of disease activity. These results demonstrate a prominent pathological role of Tc2 in SLE. While Tc1, Tc17, Tc17.1, Tfc subsets probably have regulatory functions

1. Nasonov EL (ed.). Rheumatology. Russian clinical recommendations. Moscow:GEOTAR-Media;2017 (In Russ.)

2. Nasonov E.L. Prospects for anti-B-cell therapy in rheumatology. Nauchno-Prakticheskaya Revmatologia = Rheumatology Science and Practice. 2018;56(5):539-548 (In Russ.) doi: 10.14412/1995-4484-2018-539-548

3. Shaduro DV, Beloglazov VA, Gordienko AI. Major lymphocyte subpopulations in patients with systemic lupus erythematosus and their associations with cellular and humoral antiendotoxin immunity. Medical Immunology (Russia). 2015;17(4):359-366 (In Russ.) doi: 10.15789/1563-0625-2015-4-359-366

4. Blanco P, Pitard V, Viallard JF, Taupin JL, Pellegrin JL, Moreau JF. Increase in activated CD8+ T lymphocytes expressing perforin and granzyme B correlates with disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 2005;52:201-211. doi: 10.1002/art.20745

5. Couzi L, Merville P, Deminière C, Moreau JF, Combe C, Pellegrin JL, et al. Predominance of CD8+ T lymphocytes among periglomerular infiltrating cells and link to the prognosis of class III and class IV lupus nephritis. Arthritis Rheum. 2007;56(7):2362-2370. doi: 10.1002/art.22654

6. Dolff S, Abdulahad WH, Arends S, van Dijk MC, Limburg PC, Kallenberg CG, et al. Urinary CD8+ T-cell counts discriminate between active and inactive lupus nephritis. Arthritis Res Ther. 2013;15(1):R36. doi: 10.1186/ar4189

7. Klocke J, Kopetschke K, Grießbach AS, Langhans V, Humrich JY, Biesen R, et al. Mapping urinary chemokines in human lupus nephritis: Potentially redundant pathways recruit CD4+ and CD8+ T cells and macrophages. Eur J Immunol. 2017;47(1):180-192. doi: 10.1002/eji.201646387

8. Yuan S, Zeng Y, Li J, Wang C, Li W, He Z, et al. Phenotypical changes and clinical significance of CD4+/CD8+ T cells in SLE. Lupus Sci Med. 2022;9(1):e000660. doi: 10.1136/lupus-2022-000660

9. St Paul M, Ohashi PS. The roles of CD8+ T cell subsets in antitumor immunity. Trends Cell Biol. 2020;30(9):695-704. doi: 10.1016/j.tcb.2020.06.003

10. Fousteri G, Kuka M. The elusive identity of CXCR5+ CD8 T cells in viral infection and autoimmunity: Cytotoxic, regulatory, or helper cells? Mol Immunol. 2020;119:101-105. doi: 10.1016/j.molimm.2020.01.007

11. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheumatol. 2019;71(9):1400-1412. doi: 10.1002/art.40930

12. Kudryavtsev IV, Borisov AG, Krobinets II, Savchenko AA, Serebriakova MK, Totolian AA. Chemokine receptors at distinct differentiation stages of T-helpers from peripheral blood. Medical Immunology (Russia). 2016;18(3):239-250 (In Russ.) doi: 10.15789/1563-0625-2016-3-239-250

13. Loyal L, Warth S, Jürchott K, Mölder F, Nikolaou C, Babel N, et al. SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8+ T cells. Nat Commun. 2020;11(1):6357. doi: 10.1038/s41467-020-19002-6

14. Kudryavtsev IV, Arsentieva NA, Korobova ZR, Isakov DV, Rubinstein AA, Batsunov OK, et al. Heterogenous CD8+ T cell maturation and ‘polarization’ in acute and convalescent COVID19 patients. Viruses. 2022;14(9):1906. doi: 10.3390/v14091906

15. Chen J, Ding L, Meng W, Yang J, Yan C, Xie J, et al. Vincristinecyclophosphamide combination therapy positively affects T-cell subset distribution in systemic lupus erythematosus patients. Med Sci Monit. 2015;21:505-510. doi: 10.12659/MSM.893271

16. Chen PM, Tsokos GC. The role of CD8+ T-cell systemic lupus erythematosus pathogenesis: An update. Curr Opin Rheumatol. 2021;33(6):586-591. doi:10.1097/BOR.0000000000000815

17. Postal M, Appenzeller S. The role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of systemic lupus erythematosus. Cytokine. 2011;56(3):537-543. doi: 10.1016/j.cyto.2011.08.026

18. Jacob CO, McDevitt HO. Tumor necrosis factor-alpha in murine autoimmune ‘lupus’ nephritis. Nature. 1988;331:356-358. doi: 10.1038/331356a0

19. López P, Gutiérrez C, Suárez A. IL-10 and TNFα genotypes in SLE. J Biomed Biotechnol. 2010;2010:838390. doi: 10.1155/2010/838390

20. Bridgewood C, Wittmann M, Macleod T, Watad A, Newton D, Bhan K, et al. T helper 2 IL-4/IL-13 dual blockade with dupilumab is linked to some emergent T helper 17-type diseases, including seronegative arthritis and enthesitis/enthesopathy, but not to humoral autoimmune diseases. J Invest Dermatol. 2022;142(10):2660-2667. doi: 10.1016/j.jid.2022.03.013