Abstract
In this study we demonstrate a new form of immunoregulation: engagement on CD4+ T cells of the complement regulator CD46 promoted the effector potential of T helper type 1 cells (T H 1 cells), but as interleukin 2 (IL-2) accumulated, it switched cells toward a regulatory phenotype, attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 after interaction of the CD46 tail with the serine-threonine kinase SPAK. Activated CD4 + T cells produced CD46 ligands, and blocking CD46 inhibited IL-10 production. Furthermore, CD4+ T cells in rheumatoid arthritis failed to switch, consequently producing excessive interferon-γ (IFN-γ). Finally, γδ T cells, which rarely produce IL-10, expressed an alternative CD46 isoform and were unable to switch. Nonetheless, coengagement of T cell antigen receptor (TCR) γδ and CD46 suppressed effector cytokine production, establishing that CD46 uses distinct mechanisms to regulate different T cell subsets during an immune response.
| Original language | English |
|---|---|
| Journal | Nature Immunology |
| Volume | 11 |
| Issue number | 9 |
| Pages (from-to) | 862-871 |
| Number of pages | 10 |
| ISSN | 1529-2908 |
| DOIs | |
| Publication status | Published - 09.2010 |
Funding
We thank H. Jomaa (JustusLiebigUniversität) for HMBPP; K. Murphy for advice and discussions; and C. Hawrylowicz for help with manuscript revision. Supported by the American Asthma Foundation (formerly Sandler Program for Asthma Research; J.P.A. and C.K.), the Wellcome Trust (A.H. and A.R.), Cancer Research UK (A.H. and P.V.), the US National Institutes of Health (AI037618 to J.P.A.), the Medical Research Council Centre for Transplantation, Guy’s Hospital, King’s College (G.L. and C.K.) and the Department of Health, National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (G.L.F., A.H and C.K).
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
