Heterogeneity of circulating CXCR5-PD-1 ^hi Tph cells in patients of type 2 and type 1 diabetes in Chinese population.

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 9200299 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-5233 (Electronic) Linking ISSN: 09405429 NLM ISO Abbreviation: Acta Diabetol Subsets: MEDLINE

Publication: Berlin : Springer Verlag
Original Publication: Berlin : Springer International, c1991-

Diabetes Mellitus, Type 1* ; Diabetes Mellitus, Type 2*/epidemiology ; T-Lymphocytes, Helper-Inducer*; Humans ; Autoantibodies ; East Asian People ; Programmed Cell Death 1 Receptor ; Receptors, CXCR5

Aims: Circulating peripheral helper T (Tph) cells are shown to promote the progression of autoimmune diseases. However, the role of Tph cells in inflammatory diseases such as type 2 diabetes mellitus (T2DM) and the differences between T2DM and autoimmune diabetes remain unclear.
Methods: We recruited 92 T2DM patients, 106 type 1 diabetes mellitus (T1DM) patients and 84 healthy control individuals. Peripheral blood mononucleated cells were isolated and examined by multicolor flow cytometry. We further evaluated the correlations between circulating Tph cells and clinical biochemical parameters, islet function, disease progression and islet autoantibodies.
Results: Circulating Tph cells were significantly higher in both T2DM and T1DM patients than in healthy control individuals. A significant positive correlation was observed between Tph cells and B cells in T1DM patients and overweight T2DM patients. Furthermore, Tph cells were negatively correlated with the area under the C-peptide curve (C-PAUC), and Tph cells were significantly positively correlated with fasting glucose and glycated hemoglobin levels in T2DM patients. However, no correlation was found between Tph cells and the above clinical indicators in T1DM patients. The frequency of Tph cells positively correlated with the titer of GAD autoantibodies and duration of disease in T1DM patients. In addition, we demonstrated that the frequency of Tph cells was decreased after rituximab therapy in T1DM patients.
Conclusions: Circulating Tph cells are associated with blood glucose levels and islet function in T2DM patients. In T1DM patients, circulating Tph cells are associated with B cells and islet autoantibodies. This may suggest that Tph cells have different pathogenic mechanisms in the two types of diabetes.
Clinical Trial Information: http://ClinicalTrials.gov NCT01280682 (registered July, 2010).
(© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Donath MY, Schumann DM, Faulenbach M, Ellingsgaard H, Perren A, Ehses JA (2008) Islet inflammation in type 2 diabetes: from metabolic stress to therapy. Diabetes Care 31(Suppl 2):S161-164. https://doi.org/10.2337/dc08-s243. (PMID: 10.2337/dc08-s24318227479)
Donath MY, Böni-Schnetzler M, Ellingsgaard H, Ehses JA (2009) Islet inflammation impairs the pancreatic beta-cell in type 2 diabetes. Physiology (Bethesda) 24:325–331. https://doi.org/10.1152/physiol.00032.2009. (PMID: 10.1152/physiol.00032.200919996363)
Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107. https://doi.org/10.1038/nri2925. (PMID: 10.1038/nri292521233852)
Brooks-Worrell B, Palmer JP (2012) Immunology in the Clinic Review Series; focus on metabolic diseases: development of islet autoimmune disease in type 2 diabetes patients: potential sequelae of chronic inflammation. Clin Exp Immunol 167:40–46. https://doi.org/10.1111/j.1365-2249.2011.04501.x. (PMID: 10.1111/j.1365-2249.2011.04501.x221328833248085)
Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11:85–97. https://doi.org/10.1038/nri2921. (PMID: 10.1038/nri2921212529893518031)
Asghar A, Sheikh N (2017) Role of immune cells in obesity induced low grade inflammation and insulin resistance. Cell Immunol 315:18–26. https://doi.org/10.1016/j.cellimm.2017.03.001. (PMID: 10.1016/j.cellimm.2017.03.00128285710)
SantaCruz-Calvo S, Bharath L, Pugh G, SantaCruz-Calvo L, Lenin RR, Lutshumba J et al (2022) Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities. Nat Rev Endocrinol 18:23–42. https://doi.org/10.1038/s41574-021-00575-1. (PMID: 10.1038/s41574-021-00575-134703027)
McLaughlin T, Liu LF, Lamendola C, Shen L, Morton J, Rivas H et al (2014) T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol 34:2637–2643. https://doi.org/10.1161/atvbaha.114.304636. (PMID: 10.1161/atvbaha.114.304636253417984445971)
Goel A, Chiu H, Felton J, Palmer JP, Brooks-Worrell B (2007) T-cell responses to islet antigens improves detection of autoimmune diabetes and identifies patients with more severe beta-cell lesions in phenotypic type 2 diabetes. Diabetes 56:2110–2115. https://doi.org/10.2337/db06-0552. (PMID: 10.2337/db06-055217473222)
Brooks-Worrell BM, Boyko EJ, Palmer JP (2014) Impact of islet autoimmunity on the progressive β-cell functional decline in type 2 diabetes. Diabetes Care 37:3286–3293. https://doi.org/10.2337/dc14-0961. (PMID: 10.2337/dc14-0961252397834237971)
Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y et al (2017) Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542:110–114. https://doi.org/10.1038/nature20810. (PMID: 10.1038/nature20810281507775349321)
Fortea-Gordo P, Nuño L, Villalba A, Peiteado D, Monjo I, Sánchez-Mateos P et al (2019) Two populations of circulating PD-1hiCD4 T cells with distinct B cell helping capacity are elevated in early rheumatoid arthritis. Rheumatology (Oxford) 58:1662–1673. https://doi.org/10.1093/rheumatology/kez169. (PMID: 10.1093/rheumatology/kez16931056653)
Yoshitomi H, Ueno H (2021) Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases. Cell Mol Immunol 18:523–527. https://doi.org/10.1038/s41423-020-00529-z. (PMID: 10.1038/s41423-020-00529-z32868910)
Wacleche VS, Wang R, Rao DA (2022) Identification of T Peripheral Helper (Tph) Cells. Methods Mol Biol 2380:59–76. https://doi.org/10.1007/978-1-0716-1736-6_6. (PMID: 10.1007/978-1-0716-1736-6_634802122)
Rao DA (2018) T Cells That Help B Cells in Chronically Inflamed Tissues. Front Immunol 9:1924. https://doi.org/10.3389/fimmu.2018.01924. (PMID: 10.3389/fimmu.2018.01924301907216115497)
Bocharnikov AV, Keegan J, Wacleche VS, Cao Y, Fonseka CY, Wang G, et al. (2019) PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI Insight 4. https://doi.org/10.1172/jci.insight.130062.
Verstappen GM, Meiners PM, Corneth OBJ, Visser A, Arends S, Abdulahad WH et al (2017) Attenuation of Follicular Helper T Cell-Dependent B Cell Hyperactivity by Abatacept Treatment in Primary Sjögren’s Syndrome. Arthritis Rheumatol 69:1850–1861. https://doi.org/10.1002/art.40165. (PMID: 10.1002/art.4016528564491)
Yabe H, Kamekura R, Yamamoto M, Murayama K, Kamiya S, Ikegami I et al (2021) Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease. Mod Rheumatol 31:249–260. https://doi.org/10.1080/14397595.2020.1719576. (PMID: 10.1080/14397595.2020.171957632023137)
Wang X, Li T, Si R, Chen J, Qu Z, Jiang Y (2020) Increased frequency of PD-1(hi)CXCR5(-) T cells and B cells in patients with newly diagnosed IgA nephropathy. Sci Rep 10:492. https://doi.org/10.1038/s41598-019-57324-8. (PMID: 10.1038/s41598-019-57324-8319491936965632)
Choi JY, Ho JH, Pasoto SG, Bunin V, Kim ST, Carrasco S et al (2015) Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis Rheumatol 67:988–999. https://doi.org/10.1002/art.39020. (PMID: 10.1002/art.39020255811134450082)
Ekman I, Ihantola EL, Viisanen T, Rao DA, Näntö-Salonen K, Knip M et al (2019) Circulating CXCR5(-)PD-1(hi) peripheral T helper cells are associated with progression to type 1 diabetes. Diabetologia 62:1681–1688. https://doi.org/10.1007/s00125-019-4936-8. (PMID: 10.1007/s00125-019-4936-8312705836677711)
(2018) 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care 41: S13-s27. https://doi.org/10.2337/dc18-S002.
American Diabetes A (2018) 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care 41:S13–S27. https://doi.org/10.2337/dc18-S002. (PMID: 10.2337/dc18-S002)
Zhu M, Xu K, Chen Y, Gu Y, Zhang M, Luo F et al (2019) Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study. Diabetes Care 42:1414–1421. https://doi.org/10.2337/dc18-2023. (PMID: 10.2337/dc18-202331152121)
Xu B, Wang S, Zhou M, Huang Y, Fu R, Guo C et al (2017) The ratio of circulating follicular T helper cell to follicular T regulatory cell is correlated with disease activity in systemic lupus erythematosus. Clin Immunol 183:46–53. https://doi.org/10.1016/j.clim.2017.07.004. (PMID: 10.1016/j.clim.2017.07.004287099145673570)
Xu X, Shen M, Zhao R, Cai Y, Jiang H, Shen Z et al (2019) Follicular regulatory T cells are associated with beta-cell autoimmunity and the development of type 1 diabetes. J Clin Endocrinol Metab. https://doi.org/10.1210/jc.2019-00093. (PMID: 10.1210/jc.2019-00093313935697062410)
Force CMaGoCoT (2002) Predictive values of body mass index and waist circumference to risk factors of related diseases in Chinese adult population. Chin J Epidemiol 23:6.
Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R et al (2009) Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 361:2143–2152. https://doi.org/10.1056/NEJMoa0904452. (PMID: 10.1056/NEJMoa0904452199402996410357)
Manzo A, Vitolo B, Humby F, Caporali R, Jarrossay D, Dell’accio F et al (2008) Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint. Arthritis Rheum 58:3377–3387. https://doi.org/10.1002/art.23966. (PMID: 10.1002/art.2396618975336)
Wu EL, Kazzi NG, Lee JM (2013) Cost-effectiveness of screening strategies for identifying pediatric diabetes mellitus and dysglycemia. JAMA Pediatr 167:32–39. https://doi.org/10.1001/jamapediatrics.2013.419. (PMID: 10.1001/jamapediatrics.2013.41923403824)
Christophersen A, Lund EG, Snir O, Sola E, Kanduri C, Dahal-Koirala S et al (2019) Distinct phenotype of CD4(+) T cells driving celiac disease identified in multiple autoimmune conditions. Nat Med 25:734–737. https://doi.org/10.1038/s41591-019-0403-9. (PMID: 10.1038/s41591-019-0403-9309111366647859)
Smith FL, Baumgarth N (2019) B-1 cell responses to infections. Curr Opin Immunol 57:23–31. https://doi.org/10.1016/j.coi.2018.12.001. (PMID: 10.1016/j.coi.2018.12.001306856926521837)
Cencioni MT, Mattoscio M, Magliozzi R, Bar-Or A, Muraro PA (2021) B cells in multiple sclerosis - from targeted depletion to immune reconstitution therapies. Nat Rev Neurol 17:399–414. https://doi.org/10.1038/s41582-021-00498-5. (PMID: 10.1038/s41582-021-00498-534075251)
Sahputra R, Ruckerl D, Couper KN, Muller W, Else KJ (2019) The Essential Role Played by B Cells in Supporting Protective Immunity Against Trichuris muris Infection Is by Controlling the Th1/Th2 Balance in the Mesenteric Lymph Nodes and Depends on Host Genetic Background. Front Immunol 10:2842. https://doi.org/10.3389/fimmu.2019.02842. (PMID: 10.3389/fimmu.2019.02842319211206915098)
Khan IM, Perrard XY, Brunner G, Lui H, Sparks LM, Smith SR et al (2015) Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance. Int J Obes (Lond) 39:1607–1618. https://doi.org/10.1038/ijo.2015.104. (PMID: 10.1038/ijo.2015.10426041698)
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M et al (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920. https://doi.org/10.1038/nm.1964. (PMID: 10.1038/nm.196419633658)
Shimobayashi M, Albert V, Woelnerhanssen B, Frei IC, Weissenberger D, Meyer-Gerspach AC et al (2018) Insulin resistance causes inflammation in adipose tissue. J Clin Invest 128:1538–1550. https://doi.org/10.1172/JCI96139. (PMID: 10.1172/JCI96139295283355873875)
Winer DA, Winer S, Chng MH, Shen L, Engleman EG (2014) B Lymphocytes in obesity-related adipose tissue inflammation and insulin resistance. Cell Mol Life Sci 71:1033–1043. https://doi.org/10.1007/s00018-013-1486-y. (PMID: 10.1007/s00018-013-1486-y24127133)

81970707 National Natural Science Foundation of China; 82270875 National Natural Science Foundation of China; 82230028 National Natural Science Foundation of China

Keywords: B cells; Peripheral helper T cells; T cells; Type 1 diabetes; Type 2 diabetes

ClinicalTrials.gov NCT01280682

0 (anti-GAD65 autoantibody)
0 (Autoantibodies)
0 (CXCR5 protein, human)
0 (PDCD1 protein, human)
0 (Programmed Cell Death 1 Receptor)
0 (Receptors, CXCR5)

Date Created: 20230306 Date Completed: 20230510 Latest Revision: 20230510

20230512

10.1007/s00592-023-02055-6

36879107