Heterogeneous CD3 expression levels in differing T cell subsets correlate with the in vivo anti-CD3-mediated T cell modulation

Andrea Valle, Giulia Barbagiovanni, Tatiana Jofra, Angela Stabilini, Louis Perol, Audrey Baeyens, Santosh Anand, Nicolas Cagnard, Nicola Gagliani, Eliane Piaggio, Manuela Battaglia

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2117-2127
Number of pages11
JournalJournal of Immunology
Volume194
Issue number5
DOIs
Publication statusPublished - Mar 1 2015

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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