Insulin-Like Growth Factor-1 Controls Type 2 T Cell-Independent B Cell Response

Abstract

The IGF-1 receptor (IGF-1R) is expressed on T and B lymphocytes, and the expression of the insulin- and IGF-1-signaling machinery undergoes defined changes throughout lineage differentiation, offering a putative role for IGF-1 in the regulation of immune responses. To study the role of the IGF-1R in lymphocyte differentiation and function in vivo, we have reconstituted immunodeficient RAG2-deficient mice with IGF-1R−/− fetal liver cells. Despite the absence of IGF-1Rs, the development and ex vivo activation of B and T lymphocytes were unaltered in these chimeric mice. By contrast, the humoral immune response to the T cell-independent type 2 Ag 4-hydroxy-3-nitrophenyl acetyl-Ficoll was significantly reduced in mice reconstituted with IGF-1R-deficient fetal liver cells, whereas responses to the T cell-dependent Ag 4-hydroxy-3-nitrophenyl acetyl-chicken globulin were normal. Moreover, in an in vitro model of T cell-independent type 2 responses, IGF-1 promoted Ig production potently upon polyvalent membrane-IgD cross-linking. These data indicate that functional IGF-1R signaling is required for T cell-independent B cell responses in vivo, defining a novel regulatory mechanism for the immune response against bacterial polysaccharides.

Dendritic Cell Differentiation and Immune Tolerance to Insulin-Related Peptides in Igf2-Deficient Mice

“…Normal development and ex vivo activation of T and B cells are observed in chimeric Rag2-deficient C57BL/6 mice reconstituted with fetal liver cells from Igf1r Ϫ/Ϫ mice. However, this model revealed an unexpected decrease of the T-independent B cell response which is important in bacterial defense mechanisms (8).…”

Aberrant Expression of the Insulin-Like Growth Factor-1 Receptor by T Cells from Patients with Graves’ Disease May Carry Functional Consequences for Disease Pathogenesis

“…With regard to B cell differentiation, IGF-1 promotes Ig production in chimeric immunodeficient mice reconstituted with IGF-1R Ϫ/Ϫ fetal liver cells (22). It also enhances T cell-independent humoral immune responses (22). These findings indicate that functional IGF-1R may be required for T cell-independent B cell responses and support its important role in B cell differentiation and Ab production.…”

“…It can bias lymphocyte development toward a Th2 phenotype by enhancing IL-10 (19), IL-4, and IL-13 synthesis (20) while inhibiting IFN-␥ function (21). With regard to B cell differentiation, IGF-1 promotes Ig production in chimeric immunodeficient mice reconstituted with IGF-1R Ϫ/Ϫ fetal liver cells (22). It also enhances T cell-independent humoral immune responses (22).…”

Insulin-Like Growth Factor-I Regulation of Immune Function: A Potential Therapeutic Target in Autoimmune Diseases?

“…B-cell development remained normal in IGF-IR-deficient chimeras, as did T-cell differentiation. In these animals, IGF-I enhanced immunoglobulin production, an effect that proved independent of B-cell proliferation (Baudler et al, 2005). Kimata and Yoshida (1994a,b) examined human B cells from individuals undergoing tonsillectomies for chronic tonsillitis.…”

“…Human lymphoblasts synthesize IGFBP2 and IGFBP4 (Neely et al, 1991). Baudler et al (2005) reconstituted Rag2-deficient C57BL/6 mice with fetal liver cells from IGF-IR(Ϫ/Ϫ) mice. T-cell-independent humoral responses to the type 2 antigen 4-hydroxy-3-nitrophenyl acetyl Ficoll were substantially diminished, whereas those against the T-cell-dependent antigen 4-hydroxy-3-nitrophenyl acetyl-chicken globulin were unaltered.…”