Increased T cell autoreactivity in the absence of CD40-CD40 ligand interactions: a role of CD40 in regulatory T cell development.
Mutations in the CD40 ligand (CD40L) gene lead to X-linked immunodeficiency with hyper-IgM, which is often associated with autoimmune diseases. To determine the contribution of defective CD40-CD40L interactions to T cell autoreactivity, we reconstituted CD40-CD40L interactions by transferring T cells from CD40-deficient mice to syngenic athymic nude mice and assessed autoimmunity. T cells from CD40-deficient mice triggered autoimmune diseases accompanied with elevations of various autoantibodies, while those from wild-type mice did not. In CD40-deficient mice, the CD25(+) CD45RB(low) CD4(+) subpopulation which regulates T cell autoreactivity was markedly reduced. CD40-deficient APCs failed to induce T regulatory cells 1 producing high levels of an inhibitory cytokine, IL-10 in vitro. Furthermore, autoimmune development was inhibited when T cells from CD40-deficient mice were cotransferred with CD45RB(low) CD4(+) T cells from wild-type mice or with T regulatory cells 1 induced on CD40-expressing APCs. Collectively, our results indicate that CD40-CD40L interactions contribute to negative regulation of T cell autoreactivity and that defective interactions can lead to autoimmunity.
Kumanogoh
A
A
Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Japan.
Wang
X
X
Lee
I
I
Watanabe
C
C
Kamanaka
M
M
Shi
W
W
Yoshida
K
K
Sato
T
T
Habu
S
S
Itoh
M
M
Sakaguchi
N
N
Sakaguchi
S
S
Kikutani
H
H
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023201:CD40 Ligand / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008819:Mice, Nude; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation
D001323:Autoantibodies; D001324:Autoantigens; D019013:CD40 Antigens; D015375:Receptors, Interleukin-2; D023201:CD40 Ligand; D017493:Leukocyte Common Antigens