TIM-1 signaling in B cells regulates antibody production

Author:

TIM-1 signaling in B cells regulates antibody production (1)

Members of the T cell Ig and mucin (TIM) family have recently been implicated in the control of T cell-mediated immune responses. TIM-1 expression on anti-IgM- or anti-CD40-stimulated splenic B cells, which was further up-regulated by the combination of anti-IgM and anti-CD40 Abs. In vitro stimulation of activated B cells by anti-TIM-1 mAb enhanced proliferation and expression of a plasma cell marker syndecan-1 (CD138). When immunized with T-dependent antigen OVA, serum levels of OVA-specific IgG2b, IgG3, and IgE Abs were significantly increased in the anti-TIM-1-treated mice.

The T cell immunoglobulin and mucin domain (TIM) family has recently been implicated in the regulation of T cell activation and immune responses. Four proteins (TIM-1, -2, -3, and -4) have been identified in mice, and TIM-1 and TIM-3 have polymorphism at the protein level, represented by BALB/c-type and B6-type. The expression of TIM-1 has been found on Th2 cells, mast cells, NKT cells, and tubular epithelial cells of the kidney. Administration of agonistic anti-TIM-1 mAb in vivo increased antigen-specific T cell proliferation and production of IL-4 and IFN-g.

Purified small resting B cells were stimulated with the combination of anti-IgM, anti-CD40, and IL-4 in the presence of anti-TIM-1 mAb or control rat IgG. Culture supernatants were harvested on day 7. Ig secretion was not changed when B cells were only treated with anti-TIM-1 mAb or control IgG. Supernatants from the anti-TIM-1 mAb culture with anti-IgM, anti-CD40, or anti-IgM + anti-CD40 stimulation showed higher IgG2b levels as compared to the control IgG cultures. In addition, supernatants from the anti-TIM-1 mAb cultures with anti-CD40 + IL-4 stimulation showed higher IgG3 levels as compared to the control IgG culture.

Mice were i.p. immunized with TNP-Ficoll and administrated with anti-TIM-1 mAb or control rat IgG on days 1 and 3. Serum levels of anti-TNP Abs were determined on day 7 by isotype-specific ELISA. Serum levels of TNP-specific IgG1, IgG2b, and IgG3 Abs were slightly, but not significantly, increased in the anti-TIM-1-treated mice as compared to the control IgG-treated mice. On the other hand, mice were i.p. immunized with OVA/alum on days 0 and 14 and administrated with anti-TIM-1 mAb or control IgG every 3 days from day 0 to day 18. Serum levels of anti-OVA Abs were determined on day 21 by ELISA. All isotypes of OVA-specific Abs were increased in the anti-TIM-1-treated mice as compared to the control IgG-treated mice. OVA-specific IgG2b, IgG3, and IgE Abs were significantly increased in the anti-TIM-1- treated mice. TIM-1 signaling regulates antibody production by B cells autonomously and through T-B cell interaction.

In vitro stimulation of activated B cells with anti-TIM-1 mAb enhanced proliferation and Ig production. The expression of B220, CD19, CD21, and MHC class II was down-regulated by anti- TIM-1 mAb stimulation, but the expression of syndecan-1 (CD138) was upregulated. The TIM1/TIM-1L interaction can participate in the B–T cell interaction. Administration of anti-TIM-2 mAbs in a collagen-induced arthritis significantly exacerbated disease by enhancement of B cell activation and Ab production. Mouse TIM-2 is also highly expressed on splenic B cells after stimulation with anti-IgM and anti-CD40 in vitro. The effect of anti-TIM-1 mAb treatment on the development of collagen-induced arthritis and asthma in mouse models would be the next studies.

1. J. Ma, Y. Usui, K. Takeda, N. Harada, H. Yagita, K. Okumura, H. Akiba, TIM-1 signaling in B cells regulates antibody production. Biochem. Biophys. Res. Commun. 406, 223–228 (2011).

Leave a Reply

Your email address will not be published. Required fields are marked *