A specific CD4 epitope bound by tregalizumab mediates activation of regulatory T cells by a unique signaling pathway
نویسندگان
چکیده
CD4(+)CD25(+) regulatory T cells (Tregs) represent a specialized subpopulation of T cells, which are essential for maintaining peripheral tolerance and preventing autoimmunity. The immunomodulatory effects of Tregs depend on their activation status. Here we show that, in contrast to conventional anti-CD4 monoclonal antibodies (mAbs), the humanized CD4-specific monoclonal antibody tregalizumab (BT-061) is able to selectively activate the suppressive properties of Tregs in vitro. BT-061 activates Tregs by binding to CD4 and activation of signaling downstream pathways. The specific functionality of BT-061 may be explained by the recognition of a unique, conformational epitope on domain 2 of the CD4 molecule that is not recognized by other anti-CD4 mAbs. We found that, due to this special epitope binding, BT-061 induces a unique phosphorylation of T-cell receptor complex-associated signaling molecules. This is sufficient to activate the function of Tregs without activating effector T cells. Furthermore, BT-061 does not induce the release of pro-inflammatory cytokines. These results demonstrate that BT-061 stimulation via the CD4 receptor is able to induce T-cell receptor-independent activation of Tregs. Selective activation of Tregs via CD4 is a promising approach for the treatment of autoimmune diseases where insufficient Treg activity has been described. Clinical investigation of this new approach is currently ongoing.
منابع مشابه
Tregalizumab – A Monoclonal Antibody to Target Regulatory T Cells
Regulatory T cells (Tregs) represent a subpopulation of CD4(+) T cells, which are essential for the maintenance of immunological tolerance. The absence or dysfunction of Tregs can lead to autoimmunity and allergies. The restoration of functional Tregs and/or Treg cell numbers represents a novel and attractive approach for the treatment of autoimmune diseases, e.g., rheumatoid arthritis (RA). Th...
متن کاملHigh thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab
The humanized non-depleting anti-CD4 monoclonal antibody Tregalizumab (BT-061) is able to selectively activate the suppressive function of regulatory T cells and has been investigated up to phase IIb in clinical trials in patients suffering from rheumatoid arthritis (RA). A pharmacokinetic-pharmacodynamic model based on clinical data from RA and healthy volunteers, which used the cell surface C...
متن کاملHuman Leukocyte Antigen-G Expression on Dendritic Cells Induced by Transforming Growth Factor-β1 and CD4+ T Cells Proliferation
Background: During antigen capture and processing, mature dendritic cells (DC) express large amounts of peptide-MHC complexes and accessory molecules on their surface. DC are antigen-presenting cells that have an important role in tolerance and autoimmunity. The transforming growth factor-beta1 (TGF-β1) cytokine has a regulatory role on the immune and non-immune cells. The aim of this study is ...
متن کاملB and T Lymphocyte Attenuator is a Target of miR-155 during Naive CD4+ T Cell Activation
Background: MicroRNA-155 (miR-155) is upregulated during T cell activation, but the exact mechanisms by which it influences CD4+ T cell activation remain unclear. Objective: To examine whether the B and T lymphocyte attenuator (BTLA) is a target of miR-155 during naïve CD4+ T cell activation. Methods: Firefly luciferase reporter plasmids pEZX-MT01-wild-type-BTLA and pEZX-MT01-mutant-BTLA were ...
متن کاملAKT family and miRNAs expression in IL-2-induced CD4+T cells
Objective(s): Study of non-coding RNAs is considerable to elucidate principal biological questions or design new therapeutic strategies. miRNAs are a group of non-coding RNAs that their functions in PI3K/AKT signaling and apoptosis pathways after T cell activation is not entirely clear. Herein, miRNAs expression and their putative targets in the mentioned pathways were studied in the activated ...
متن کامل