Heterogeneous CD3 expression levels in differing T cell subsets correlate with the in vivo anti-CD3-mediated T cell modulation
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Heterogeneous CD3 expression levels in differing T cell subsets correlate with the in vivo anti-CD3-mediated T cell modulation. / Valle, Andrea; Barbagiovanni, Giulia; Jofra, Tatiana; Stabilini, Angela; Perol, Louis; Baeyens, Audrey; Anand, Santosh; Cagnard, Nicolas; Gagliani, Nicola; Piaggio, Eliane; Battaglia, Manuela.
in: J IMMUNOL, Jahrgang 194, Nr. 5, 01.03.2015, S. 2117-27.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Heterogeneous CD3 expression levels in differing T cell subsets correlate with the in vivo anti-CD3-mediated T cell modulation
AU - Valle, Andrea
AU - Barbagiovanni, Giulia
AU - Jofra, Tatiana
AU - Stabilini, Angela
AU - Perol, Louis
AU - Baeyens, Audrey
AU - Anand, Santosh
AU - Cagnard, Nicolas
AU - Gagliani, Nicola
AU - Piaggio, Eliane
AU - Battaglia, Manuela
N1 - Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - The tolerogenic anti-CD3ε monoclonal Abs (anti-CD3) are promising compounds for the treatment of type 1 diabetes. Anti-CD3 administration induces transient T cell depletion both in preclinical and in clinical studies. Notably, the said depletion mainly affects CD4(+) but not CD8(+) T cells. Moreover, type 1 diabetes reversal in preclinical models is accompanied by the selective expansion of CD4(+)Foxp3(+) T regulatory (Treg) cells, which are fundamental for the long-term maintenance of anti-CD3-mediated tolerance. The mechanisms that lead to this immune-shaping by affecting mainly CD4(+) T effector cells while sparing CD4(+)Foxp3(+) Treg cells have still to be fully elucidated. This study shows that CD3 expression levels differ from one T cell subset to another. CD4(+)Foxp3(-) T cells contain higher amounts of CD3 molecules than do CD4(+)Foxp3(+) and CD8(+) T cells in both mice and humans. The said differences correlate with the anti-CD3-mediated immune resetting that occurs in vivo after anti-CD3 administration in diabetic NOD mice. Additionally, transcriptome analysis demonstrates that CD4(+)Foxp3(+) Treg cells are significantly less responsive than are CD4(+)Foxp3(-) T cells to anti-CD3 treatment at a molecular level. Thus, heterogeneity in CD3 expression seems to confer to the various T cell subsets differing susceptibility to the in vivo tolerogenic anti-CD3-mediated modulation. These data shed new light on the molecular mechanism that underlies anti-CD3-mediated immune resetting and thus may open new opportunities to improve this promising treatment.
AB - The tolerogenic anti-CD3ε monoclonal Abs (anti-CD3) are promising compounds for the treatment of type 1 diabetes. Anti-CD3 administration induces transient T cell depletion both in preclinical and in clinical studies. Notably, the said depletion mainly affects CD4(+) but not CD8(+) T cells. Moreover, type 1 diabetes reversal in preclinical models is accompanied by the selective expansion of CD4(+)Foxp3(+) T regulatory (Treg) cells, which are fundamental for the long-term maintenance of anti-CD3-mediated tolerance. The mechanisms that lead to this immune-shaping by affecting mainly CD4(+) T effector cells while sparing CD4(+)Foxp3(+) Treg cells have still to be fully elucidated. This study shows that CD3 expression levels differ from one T cell subset to another. CD4(+)Foxp3(-) T cells contain higher amounts of CD3 molecules than do CD4(+)Foxp3(+) and CD8(+) T cells in both mice and humans. The said differences correlate with the anti-CD3-mediated immune resetting that occurs in vivo after anti-CD3 administration in diabetic NOD mice. Additionally, transcriptome analysis demonstrates that CD4(+)Foxp3(+) Treg cells are significantly less responsive than are CD4(+)Foxp3(-) T cells to anti-CD3 treatment at a molecular level. Thus, heterogeneity in CD3 expression seems to confer to the various T cell subsets differing susceptibility to the in vivo tolerogenic anti-CD3-mediated modulation. These data shed new light on the molecular mechanism that underlies anti-CD3-mediated immune resetting and thus may open new opportunities to improve this promising treatment.
KW - Adolescent
KW - Animals
KW - Antibodies, Monoclonal, Humanized
KW - CD3 Complex
KW - CD4-Positive T-Lymphocytes
KW - CD8-Positive T-Lymphocytes
KW - Child
KW - Child, Preschool
KW - Diabetes Mellitus, Type 1
KW - Female
KW - Forkhead Transcription Factors
KW - Gene Expression Regulation
KW - Genetic Heterogeneity
KW - Humans
KW - Hypoglycemic Agents
KW - Immune Tolerance
KW - Immunologic Factors
KW - Lymphocyte Depletion
KW - Male
KW - Mice
KW - Mice, Inbred NOD
KW - Signal Transduction
KW - T-Lymphocyte Subsets
KW - Young Adult
KW - Journal Article
U2 - 10.4049/jimmunol.1401551
DO - 10.4049/jimmunol.1401551
M3 - SCORING: Journal article
C2 - 25646305
VL - 194
SP - 2117
EP - 2127
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 5
ER -