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T1D progression is associated with loss of CD3⁺CD56⁺ regulatory T cells that control CD8⁺ T cell effector functions.

ABSTRACT: An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (T_R3-56), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating T_R3-56 cells is associated with reduced ?-cell function and with the presence of diabetic ketoacidosis. As autoreactive CD8⁺ T cells mediate disruption of insulin-producing ?-cells^1-3, we demonstrate that T_R3-56 cells can suppress CD8⁺ T cell functions in vitro by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of T_R3-56 cells are also altered in T1D children. Together, our findings indicate that T_R3-56 cells constitute a regulatory cell population that controls CD8⁺ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D.

SUBMITTER: Terrazzano G

PROVIDER: S-EPMC7272221 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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T1D progression is associated with loss of CD3+CD56+ regulatory T cells that control CD8+ T cell effector functions.

Terrazzano Giuseppe G Bruzzaniti Sara S Rubino Valentina V Santopaolo Marianna M Palatucci Anna Teresa AT Giovazzino Angela A La Rocca Claudia C de Candia Paola P Puca Annibale A Perna Francesco F Procaccini Claudio C De Rosa Veronica V Porcellini Chiara C De Simone Salvatore S Fattorusso Valentina V Porcellini Antonio A Mozzillo Enza E Troncone Riccardo R Franzese Adriana A Ludvigsson Johnny J Matarese Giuseppe G Ruggiero Giuseppina G Galgani Mario M

Nature metabolism 20200217 2

An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (TR3-56), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating TR3-56 cells is associated with reduced β-cell function and with th ...[more]

PMID: 32500117

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Project description:TIGIT expression on natural killer (NK) cells is associated with dysfunction during chronic HIV infection, but the phenotype and biological functions of these cells in the context of acute HIV-1 infection remain poorly understood. Here, 19 acutely infected HIV-1 patients traced at first, third and twelfth month, and age-matched patients with chronic HIV-1 infection were enrolled to investigate the phenotype and functions of TIGIT expression on NK cells. We found that TIGIT-expressing NK cells did not increase in frequency in the first, third and twelfth month of infection until chronic HIV-1 infection lasted over 2 years. The number of TIGIT+NK cells in acute infection was positively associated with HIV-1 viral load (r = 0.53, P = 0.0009). CD96 was significantly upregulated on NK cells after acute infection for 1 month and in chronic infection over 2 years, while CD226 was downregulated in chronic infection over 2 years. Further, at different stages of infection, CD96-CD226+ cells diminished among total NK cells, TIGIT+NK and TIGIT-NK cells, while CD96+CD226- cells expanded. Reduced CD96-CD226+ cells and elevated CD96+CD226- cells among NK cells especially TIGIT-NK cells, had opposite associations with viral load in the first month of infection, as well as CD4 T-cell counts in including the twelfth month and more than 2 years of chronic infection. In both HIV-1-infected individuals and healthy donors, TIGIT was predominantly expressed in NKG2A-NKG2C+NK cells, with a significantly higher proportion than in NKG2A+NKG2C-NK cells. Moreover, the frequencies of TIGIT+NK cells were positively associated with the frequencies of NKG2A-NKG2C+NK cells in acute infection (r = 0.62, P < 0.0001), chronic infection (r = 0.37, P = 0.023) and healthy donors (r = 0.36, P = 0.020). Enhanced early activation and coexpression of CD38 and HLA-DR in TIGIT+NK cells were detected compared to TIGIT-NK cells, both of which were inversely associated with the decrease in CD4 T-cell counts in both acute and chronic HIV-1 infection. The ability of TIGIT+NK cells to produce TNF-α, IFN-γ and CD107a degranulation substance were consistently weaker than that of TIGIT-NK cells in both acute and chronic infection. Moreover, the functionalities of TIGIT+NK cells were lower than those of TIGIT-NK cells, except for TNF-α-CD107a+IFN-γ-NK cells. These findings highlight the phenotype and functional characteristics of TIGIT-expressing NK cells which have poor capabilities in inhibiting HIV-1 replication and maintaining CD4 T-cell counts.

Dataset Information

T1D progression is associated with loss of CD3⁺CD56⁺ regulatory T cells that control CD8⁺ T cell effector functions.

Publications

T1D progression is associated with loss of CD3<sup>+</sup>CD56<sup>+</sup> regulatory T cells that control CD8<sup>+</sup> T cell effector functions.

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