Abstract
Background
The engagement of the complement regulatory proteins CD46 and CD3 in human CD4+ T cells induces the type 1 regulatory T cells (Tr1) and interleukin-10 (IL-10) secretion. This study aimed to elucidate the molecular changes of Tr1 cells through CD46 cytoplasmic Cyt1 tail in lupus nephritis (LN) respond to intravenous methylprednisolone (ivMP) therapy.
Methods
We enrolled 40 pediatric patients with LN and 30 healthy controls. Clinical characteristics and peripheral blood mononuclear cells were collected before and 3 days after the administration of ivMP. Kidney specimens were taken from five LN and five minimal-change nephrotic syndrome patients.
Results
We found that defective CD46-mediated T-helper type 1 contraction (IL-10 switching) is present in active LN patients. The ivMP therapy enhanced LN remission, restored the production of IL-10, increased the CD46-Cyt1/Cyt2 ratio, AKT, and cAMP-responsive element-binding protein phosphorylation, and induced migration with the expression of chemokine receptor molecules CCR4, CCR6, and CCR7 of CD3/CD46-activated Tr1 cells.
Conclusions
Pharmacologic interventions that alter the patterns of CD46-Cyt1/Cyt2 expression and the secretion of IL-10 by CD3/CD46-activated Tr1 cells can be used in patients with active LN.
Impact
-
In patients with LN, ivMP was associated with increased IL-10 production and increased CD46-Cyt1/Cyt2 ratio and AKT phosphorylation by Tr1 cells, with enhanced potential to migration in response to CCL17.
-
These results suggest that expression levels of CD46 isoforms Cyt1 and Cyt2 in CD4 + CD46 + Tr1 cells differ in patients with active LN but can be corrected by corticosteroid treatment.
-
Enhancing the expression of functional CD4 + CD46 + Tr1 cells may be a useful therapeutic approach for LN.
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References
Cope, A., Le Friec, G., Cardone, J. & Kemper, C. The Th1 life cycle: molecular control of IFN- g to IL-10 swiching. Trends Immunol. 32, 278–286 (2011).
Ohl, K. & Tenbrock, K. Inflammatory cytokines in systemic lupus erythematosus. J. Biomed. Biotechnol. 2011, 432595 (2011).
Abeler-Dörner, L. et al. Interferon-α abrogates the suppressive effect of apoptotic cells on dendritic cells in an in vitro model of systemic lupus erythematosus pathogenesis. J. Rheumatol. 40, 1683–1696 (2013).
Yan, B. et al. Dysfunctional CD4+CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum. 58, 801–812 (2008).
Trouw, L. A., Pickering, M. C. & Blom, A. M. The complement system as a potential therapeutic target in rheumatic disease. Nat. Rev. Rheumatol. 13, 538–547 (2017).
Alvarado-Sanchez, B. et al. Regulatory T cells in patients with systemic lupus erythematosus. J. Autoimmun. 27, 110–118 (2006).
Kuhn, A., Beissert, S. & Krammer, P. H. CD4(+)CD25 (+) regulatory T cells in human lupus erythematosus. Arch. Dermatol Res. 301, 71–81 (2009).
Saraiva, M. & Garra, O. A. The regulation of IL-10 production by immune cells. Net. Rev. Immunol. 10, 170–181 (2010).
Horwitz, D. A. Identity of mysterious CD4+CD25-Foxp3+ cells in SLE. Arthritis Res Ther. 12, 101 (2010).
Bonelli, M., Smolen, J. S. & Scheinecker, C. Treg and lupus. Ann. Rheum. Dis. 69, i65–i66 (2010).
Lee, H. Y., Hong, Y. K., Yun, H. J., Kim, Y. M. & Yoo, W. H. Altered frequency and migration capacity of CD4+CD25+ regulatory T cells in systemic lupus erythematosus. Rheumatology 47, 789–794 (2008).
Sawla, P., Hossain, A., Hahn, B. H. & Singh, R. P. Regulatory T cells in systemic lupus erythematosus (SLE); role of peptide tolerance. Autoimmun. Rev. 11, 611–614 (2012).
Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).
Roncarolo, M. G., Gregori, S., Bacchetta, R., Battaglia, M. & Gagliani, N. The biology of T regulatory type 1 cells and their therapeutic application in immune-mediated diseases. Immunity 49, 1004–1019 (2018).
Cardone, J. et al. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat. Immunol. 11, 862–871 (2010).
Le Friec, G. et al. The CD46-Jagged1 interaction is critical for human TH1 immunity. Nat. Immunol. 13, 1213–1221 (2012).
Kolev, M. et al. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity 42, 1033–1047 (2015).
Astier, A. L. T-cell regulation by CD46 and its relevance in multiple sclerosis. Immunology 124, 149–154 (2008).
Tsai, Y. G. et al. Functional defects of CD46-induced regulatory T cells to suppress airway inflammation in mite allergic asthma. Lab Invest. 92, 1260–1269 (2012).
Kemper, C. et al. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388–392 (2003).
Tsai, Y. G. et al. Enhanced CD46-induced regulatory T cells suppress allergic inflammation after Dermatophagoides pteronyssinus-specific immunotherapy. J. Allergy Clin. Immunol. 134, 1206–1209 (2014).
Alegretti, A. P. et al. Diminished expression of complement regulatory proteins on peripheral blood cells from systemic lupus erythematosus patients. Clin. Dev. Immunol. 2012, 725684 (2012).
Jonsen, A. et al. Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus. Arthritis Res. Ther. 13, R206 (2011).
Marie, J. C. et al. Linking innate and acquired immunity: divergent role of CD46 induces a T-regulatory cell 1 phenotype. Nature 3, 659–666 (2005).
Suárez, A., López, p, Gómez, J. & Gutiérrez, C. Enrichment of CD4+CD25high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann. Rheum. Dis. 65, 1512–1517 (2006).
Cepika, A. M., Marinic, i, Morovic-vergles, J., Soldo-Juresa, D. & Gagro, A. Effect of steroids on the frequency of regulatory T cells and expression of FOXP3 in a patient with systemic lupus erythematosus: a two-year follow-up. Lupus 16, 374–377 (2007).
Brunner, H. I., Feldman, B. M., Bombardier, C. & Silverman, E. D. Sensitivity of the systemic lupus erythematosus disease activity index, British Isles Lupus Assessment Group Index, and systemic lupus activity measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 42, 1354–1360 (1999).
Gladman, D. D., Ibanez, D. & Urowitz, M. B. Systemic lupus erythematosus disease activity index 2000. J. Rheumatol. 29, 288–291 (2002).
Tsai, Y. G., Lee, C. Y., Lin, T. Y. & Lin, C. Y. CD8+ Treg cells associated with decreasing disease activity after intravenous methylprednisolone pulse therapy in lupus nephritis with heavy proteinuria. PLoS ONE 9, e81344 (2014).
Ellinghaus, U. et al. Dysregulated CD46 shedding inferes with Th1-contraction in systemic lupus erythematosus. Eur. J. Immunol. 47, 1200–1210 (2017).
Liszewski, M. K. et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentation. Immunity 39, 1143–1157 (2013).
Lee, S. W. et al. CD46 is phosphorylated at tyrosine 354 upon infection of epithelial cells by Neisseria gonorrboeae. J. Cell Biol. 156, 951–957 (2002).
Wang, G., Liszewski, M., Chan, A. & Atkinson, J. P. Membrane cofactor protein (MCP; CD46): isoform-specific tyrosine phosphorylation. J. Immunol. 164, 1839–1846 (2000).
Ni Choileain, S. et al. The dynamic processing of CD46 intracellular domains provides a molecular rheostat for T cell activation. PLoS ONE 6, e16287 (2011).
Nangaku, M. Complement regulatory proteins in glomerular diseases. Kidney Int. 54, 1419–1428 (1998).
Tseng, M. H. et al. Serum complement factor I is associated with disease activity of systemic lupus erythematosus. Oncotarget 9, 8502–8511 (2018).
Park, M. H., Caselman, N., Ulmer, S. & Weitz, I. C. Complement-mediated thrombotic microangiopathy associated with lupus nephritis. Blood Adv. 2, 2090–2094 (2018).
Lopez, P., Gomez, J., Prado, C., Gutierrez, C. & Suarez, A. Influence of functional interleukin 10/tumor necrosis factor-alpha polymorphisms on interferon-alpha, IL-10, and regulatory T cell population in patients with systemic lupus erythematosus receiving antimalarial treatment. J. Rheumatol. 35, 1559–1566 (2008).
Yamada, M. et al. Selective accumulation of CCR4+ T lymphocytes into renal tissue of patients with lupus nephritis. Arthritis Rheum. 46, 735–740 (2002).
Alford, S. K., Longmore, G. D., Stenson, W. F. & Kemper, C. CD46-induced immunomodulatory CD4+ T cells express the adhesion molecule and chemokine receptor pattern of intestinal T cells. J. Immunol. 181, 2544–2555 (2008).
Lin, C. Y. & Tsai, Y. G. Complements and allergic asthma. Pediatr. Respirol. Crit. Care Med 3, 3–7 (2019).
Meiffren, G., Flacher, M., Azocar, O., Rabourdin-Combe, C. & Faure, M. Cutting edge: abortive proliferation of CD46-induced Tr1-like cells due to a defective Akt/Survivin signaling pathway. J. Immunol. 177, 4957–4961 (2006).
Funding
This work was partially supported by grants from the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-371-008 and MOST 107-2314-B-371-011-MY2), from Changhua Christian Hospital, Taiwan (110-CCH-IRP-030, 110-CCH-ICO-152, 106-CCH-IRP-079, 108-CCH-IRP-051; (Y_105_0246) (Y_105_0023) (Y_105_0050)), and from China Medical University Hospital, Taiwan (DMR-100-180), and Academia Sinica, Taiwan (AS-SS-111-02-1).
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Y.-G.T., J.-W.C., K.-H.H., and C.-Y.L.: conceptualized and designed the study, performed the experiments, drafted the initial manuscript, and approved the final manuscript as submitted. Y.-M.C., T.-C.S., and P.-F.C.: carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted.
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Tsai, YG., Chien, JW., Chiu, YM. et al. Lupus nephritis with corticosteroid responsiveness: molecular changes of CD46-mediated type 1 regulatory T cells. Pediatr Res 92, 1099–1107 (2022). https://doi.org/10.1038/s41390-021-01882-z
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DOI: https://doi.org/10.1038/s41390-021-01882-z
