Augmented Induction of CD4+CD25+ Treg using Monoclonal Antibodies to CD200R

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Abstract

Background.

CD200 is a transmembrane protein delivering immunoregulatory signals after engagement of CD200R. A family of CD200Rs exist (CD200R1–4) with different tissue expression and functional activity. In the presence of anti-CD200R2/3 monoclonal antibodies (mAbs), bone-marrow cells cultured in the presence of (interleukin [IL]-4+granulocyte-macrophage colony-stimulating factor) differentiate into dendritic cells (DCs), which induce CD4+CD25+Treg. The effect of these mAbs on Treg induced in anti-CD3 activated thymocyte cultures is unknown.

Methods.

BL/6 bone-marrow cells were cultured with GMC-SF and IL-4 in the presence/absence of anti-CD200Rs to generate DCs that induced Treg in C3H lymph-node T cells. Treg were also induced in anti–CD3/CD28-activated C3H thymocytes. Treg activity was assayed by (1) suppression of mixed leukocyte culture (MLC) in cultures using C3H stimulator spleen cells and BL/6 stimulator cells, and (2) by expression of the transcription factor, Foxp3.

Results.

Addition of anti-CD200R2/3 mAbs (but not anti-CD200R1) to bone-marrow cultures led to generation of DCs that induced a CD4+CD25+ (Treg) population inhibiting MLCs (C3H cells stimulated with C57BL/6 cells) in a cytotoxic T–lymphocyte-associated antigen (CTLA)-4 and transforming growth factor (TGF)–β-dependent manner. Anti-CD200R2, but not anti-R1/R3, augmented induction of Foxp3-expressing Treg from anti-CD3/CD28 activated thymocytes. Suppression in MLCs by anti-CD200R1 mAbs was dependent on IL-10 and TGF-β.

Conclusions.

Unlike anti-CD200R1, anti-CD200R2 both promotes development of DCs with capacity to induce Treg and directly augments thymocyte production of Treg.

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