Increased T Cell Autoreactivity in the Absence of CD40-CD40 Ligand Interactions: A Role of CD40 in Regulatory T Cell Development

• Published in: The Journal of immunology (1950) 2001-01, Vol.166 (1), p.353-360
• Main Authors: Kumanogoh, Atsushi, Wang, Xiaosong, Lee, Ihnsook, Watanabe, Chie, Kamanaka, Masahito, Shi, Wei, Yoshida, Kanji, Sato, Takehito, Habu, Sonoko, Itoh, Misako, Sakaguchi, Noriko, Sakaguchi, Shimon, Kikutani, Hitoshi
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - pathology; Autoantibodies - biosynthesis; Autoantibodies - blood; Autoantigens - immunology; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; CD40 antigen; CD40 Antigens - genetics; CD40 Antigens - metabolism; CD40 Antigens - physiology; CD40 Ligand - genetics; CD40 Ligand - metabolism; CD40L protein; Cell Differentiation - genetics; Cell Differentiation - immunology; Leukocyte Common Antigens - biosynthesis; Lymphocyte Count; Lymphopenia - genetics; Lymphopenia - immunology; Lymphopenia - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mice, Nude; Receptors, Interleukin-2 - biosynthesis; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; T-Lymphocyte Subsets - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.1.353

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.