Endogenous VSIG4 negatively regulates the helper T cell-mediated antibody response.
VSIG4 acts as a co-inhibitory ligand to negatively regulate T cell proliferation and cytokine production, and its expression is restricted to macrophages. We hypothesized that endogenous VSIG4 impairs helper T cell functions and then inhibits the subsequent antibody response. Isotype switching of ovalbumin (OVA)-specific antibody subclasses to IgG1, IgG2a, IgG2b, and IgG3 was enhanced in OVA-immunized VSIG4 knockout (KO) mice. 2,4,6-Trinitrophenyl hapten (TNP) - Keyhole Limpet Hemocyanin (KLH)-primed B cells cocultured with OVA-primed CD4(+) T cells from OVA-immunized VSIG4 KO mice in the presence of TNP-OVA showed enhanced isotype switching to IgG subclasses compared to those cocultured with cells isolated from OVA-immunized wild-type (WT) mice. Furthermore, the levels of CD40L expression, the frequency of memory CD4(+) T cells, and the production of isotype switching-inducing cytokines increased significantly in OVA-primed CD4(+) T cells from VSIG4 KO mice. T cells from OVA-specific T cell receptor (TCR) transgenic mice produced more IFN-γ when cocultured with macrophages from VSIG4 KO mice compared to WT mice. Thus, our results demonstrate that macrophage-associated VSIG4 plays a negative role in helper T cell-dependent isotype switching by inhibiting helper T cell activation and differentiation, and suppressing the isotype switching-inducing cytokine production in antigen-primed CD4(+) helper T cells.
Department of Microbiology and Immunology, Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Keunok
K
Jung
Department of Microbiology and Immunology, Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Su-Kil
SK
Seo
Department of Microbiology and Immunology, Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735, Republic of Korea. Electronic address: miccih@inje.ac.kr.
Inhak
I
Choi
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*
D016207:Cytokines; D011951:Receptors, Complement; C509992:VSIG4 protein, mouse; D023201:CD40 Ligand
B cells; CD40L; Co-inhibition; Isotype switching; VSIG4