1. Division of Rheumatology, Washington University School of Medicine, St Louis, Missouri 63110, USA
2. Genentech, Inc., San Francisco, California 94080, USA
3. Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
4. Graduate Program in Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA
5. Division of Pathology and Immunology, Washington University School of Medicine, and Howard Hughes Medical Institute, St Louis, Missouri 63110, USA
6. Present address: School of Medicine, 660 South Euclid Avenue, Campus Box 8045, St Louis, Missouri 63110, USA.

Correspondence to: John P. Atkinson^1,6 Correspondence and requests for materials should be addressed to J.P.A. (e-mail: Email: jatkinso@im.wustl.edu).

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 tolerance^{2, 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.