TY - JOUR
T1 - Type 1 diabetes progression is associated with loss of CD3+CD56+ regulatory T cells that control CD8+ T-cell effector functions
AU - Terrazzano, Giuseppe
AU - Bruzzaniti, Sara
AU - Rubino, Valentina
AU - Santopaolo, Marianna
AU - Palatucci, Anna Teresa
AU - Giovazzino, Angela
AU - La Rocca, Claudia
AU - de Candia, Paola
AU - Puca, Annibale
AU - Perna, Francesco
AU - Procaccini, Claudio
AU - De Rosa, Veronica
AU - Porcellini, Chiara
AU - De Simone, Salvatore
AU - Fattorusso, Valentina
AU - Porcellini, Antonio
AU - Mozzillo, Enza
AU - Troncone, Riccardo
AU - Franzese, Adriana
AU - Ludvigsson, Johnny
AU - Matarese, Giuseppe
AU - Ruggiero, Giuseppina
AU - Galgani, Mario
N1 - Funding Information:
We thank M. Montagna and all members of the IEOS-CNR for their technical support, and M. Carrara and F. Marabita for assistance in the transcriptomic analysis. This paper was supported by grants from the Juvenile Diabetes Research Foundation (grant no. 2-SRA-2018-479-S-B to M.G.; grant no. 1-SRA-2018-477-S-B to P.D.C); the European Foundation for the Study of Diabetes (EFSD/JDRF/Lilly Programme 2016 to M.G.); the National Multiple Sclerosis Society (grant no PP-1804-30725 to M.G.); Fondazione Italiana Sclerosi Multipla (grant no. 2016/R/18 to G.M.; grant no. 2018/R/4 to V.D.R.); Ministero della Salute (grant no. GR-2016-02363725 to V.D.R.); Università degli Studi di Napoli Federico II (STAR Program Linea 1–2018 to V.D.R.); European Research Council menTORingTregs grant no. 310496 to G.M.); Telethon (grant no. GGP 17086 to G.M.); Grant Fondazione Italiana Sclerosi Multipla (grant no. 2018/S/5 to G.M.); and the Italian Ministry of Health Giovani Ricercatori (grant no. GR-2016-02363749 to C. Procaccini). This work has also been supported by Italian Ministry of Health Ricerca Corrente - IRCCS MultiMedica.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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 coexpression of CD3 and CD56 molecules (TR3-56), is reduced in individuals 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 beta-cell function and with the presence of diabetic ketoacidosis. Since autoreactive CD8+ T cells mediate disruption of insulin-producing beta cells1–3, we demonstrate that TR3-56 cells can suppress CD8+ T cell functions in vitro by reducing the levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of TR3-56 cells are also altered in children with T1D. Together, our findings indicate that TR3-56 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.
AB - 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 coexpression of CD3 and CD56 molecules (TR3-56), is reduced in individuals 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 beta-cell function and with the presence of diabetic ketoacidosis. Since autoreactive CD8+ T cells mediate disruption of insulin-producing beta cells1–3, we demonstrate that TR3-56 cells can suppress CD8+ T cell functions in vitro by reducing the levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of TR3-56 cells are also altered in children with T1D. Together, our findings indicate that TR3-56 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.
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U2 - 10.1038/s42255-020-0173-1
DO - 10.1038/s42255-020-0173-1
M3 - Letter
AN - SCOPUS:85079713497
VL - 2
SP - 142
EP - 152
JO - Nature Metabolism
JF - Nature Metabolism
SN - 2522-5812
IS - 2
ER -