Letter | Published:

Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype

Abstract

The immune system must distinguish not only between self and non-self, but also between innocuous and pathological foreign antigens to prevent unnecessary or self-destructive immune responses. Unresponsiveness to harmless antigens is established through central and peripheral processes1. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance2,3, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells4. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10)5 and suppression of T-helper cells6; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype. Our findings identify an endogenous receptor-mediated event that drives Tr1 differentiation and suggest that the complement system has a previously unappreciated role in T-cell-mediated immunity and tolerance.

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Acknowledgements

We thank H. Molina, K. Liszewski, L. S. Wen and M. Denny for comments on the manuscript, and the immunology community at Washington University School of Medicine for discussions.

Author information

Correspondence to John P. Atkinson.

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Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure I: Cytokine profile of CD3/CD46 activated naïve CD4+T cells (PPT 178 kb)

Supplementary Figure II: IL-10 production induced by a natural ligand of CD46 (PPT 39 kb)

A model of CD46 activation of CD4+ T cells during antigen presentation (PPT 20 kb)

Figure Legends (DOC 19 kb)

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Further reading

Figure 1: CD3/CD46 stimulation induces IL-10 production in human peripheral blood CD4+ T lymphocytes.
Figure 2: Sorted CD3+CD4+CD45RA+CD45RO+ T cells respond to primary and secondary activation with IL-10 production.
Figure 3: Characteristics of CD3/CD46-activated, sorted CD3+CD4+CD45RA+CD45RO+ T cells.
Figure 4: Suppressive and proliferative properties of CD3/CD46-activated CD4+ T cells.

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