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Heterogeneous CD3 expression levels in differing T-cell subsets account for in vivo anti-CD3-mediated immune resetting

ABSTRACT: The tolerogenic anti-CD3 monoclonal antibodies (anti-CD3) are promising compounds for the treatment of type 1 diabetes (T1D). Anti-CD3 administration induces transient T-cell depletion both in preclinical and in clinical studies. Notably, said depletion mainly affects CD4+ but not CD8+ T cells. Moreover, T1D 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 both in mice and in humans. Said differences may explain the anti-CD3-mediated immune resetting that occurs in vivo after anti-CD3 administration in mice. In addition, transcriptome analysis demonstrates that CD4+FoxP3+ Treg cells are significantly less responsive than CD4+FoxP3- T cells to anti-CD3 treatment at molecular levels. Thus, heterogeneity in CD3 expression likely confers the various T-cell subsets differing susceptibility to in vivo tolerogenic anti-CD3-mediated modulation. This data sheds new light on the molecular mechanism that underlies anti-CD3-mediated immune resetting, and thus may open new opportunities to improve this promising treatment.

ORGANISM(S): FoxP3-GFP NOD mouse

SUBMITTER: Eliane Piaggio

PROVIDER: E-MTAB-2437 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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