Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells.
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-gamma (IFN-gamma). Finally, gammadelta 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) gammadelta and CD46 suppressed effector cytokine production, establishing that CD46 uses distinct mechanisms to regulate different T cell subsets during an immune response.
Cardone
John
J
Division of Immunology, Infection and Inflammatory Diseases, King's College London, Medical Research Council Centre for Transplantation, Guy's Hospital, London, UK.
Le Friec
Gaelle
G
Vantourout
Pierre
P
Roberts
Andrew
A
Fuchs
Anja
A
Jackson
Ian
I
Suddason
Tesha
T
Lord
Graham
G
Atkinson
John P
JP
Cope
Andrew
A
Hayday
Adrian
A
Kemper
Claudia
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016466:CHO Cells; D002478:Cells, Cultured; D003166:Complement Activating Enzymes / Q000276:immunology; D006224:Cricetinae; D003412:Cricetulus; D016207:Cytokines / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D019169:Jurkat Cells; D051916:Membrane Cofactor Protein / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000911:Antibodies, Monoclonal; C497857:CD46 protein, human; D016207:Cytokines; D007376:Interleukin-2; D051916:Membrane Cofactor Protein; D016753:Interleukin-10; D003166:Complement Activating Enzymes