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CD3-specific antibody–induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells

Abstract

Intact CD3-specific antibody transiently depletes large numbers of T cells and subsequently induces long-term immune tolerance. The underlying mechanisms for the systemic tolerance, however, remain unclear. We show here that treatment of normal mice with intact antibody to CD3 increases systemic transforming growth factor-β (TGF-β) produced by phagocytes exposed to apoptotic T cells. Among the phagocytes, macrophages and immature dendritic cells (iDCs) secrete TGF-β upon ingestion of apoptotic T cells, which induces CD4+Foxp3+ regulatory T cells in culture and contributes to immune tolerance mediated by CD3-specific antibody in vivo. In accordance with these results, depletion of macrophages and iDCs not only abrogates CD3-specific antibody–mediated prevention of myelin oligodendrocyte glycoprotein–induced acute experimental autoimmune encephalomyelitis (EAE), but also reverses the therapeutic effects of antibody to CD3 on established disease in a model of relapsing-remitting EAE. Thus, CD3-specific antibody–induced immune tolerance is associated with TGF-β production in phagocytes involved in clearing apoptotic T cells, which suggests that apoptosis is linked to active suppression in immune tolerance.

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Figure 1: CD3-specific antibody treatment increases systemic TGF-β, which requires the presence of macrophages and iDCs.
Figure 2: iDCs produce TGF-β upon ingestion of apoptotic cells and induce Foxp3+ Treg cells.
Figure 3: Macrophages and iDCs are involved in immune tolerance induced by high-dose peptide antigen in vivo.
Figure 4: Depletion of phagocytes abrogates CD3-specific antibody–mediated prevention of MOG-induced EAE.
Figure 5: Depletion of phagocytes reverses the amelioration induced by intact CD3-specific antibody on the progression of relapsing-remitting EAE in SJL mice.

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Acknowledgements

This research was supported by the Intramural Research Program of the NIDCR and NIH grant R37AI46643 (J.A.B.).

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Contributions

S.P. designed and did experiments, analyzed data and contributed to the writing of the manuscript; P.Z. designed and did experiments; Y.L. and P.S. did experiments; J.A.B. provided critical input on the EAE treatment studies and the nonmitogenic CD3-specific IgG3 antibody; W.C. initiated and directed the whole study, designed experiments, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to WanJun Chen.

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Competing interests

J.A.B. is a consultant for and has an equity stake in Macrogenics Corporation, which is developing a monoclonal antibody to CD3.

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Supplementary Figs. 1–7, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 1505 kb)

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Perruche, S., Zhang, P., Liu, Y. et al. CD3-specific antibody–induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells. Nat Med 14, 528–535 (2008). https://doi.org/10.1038/nm1749

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