Identification of CD72 as a Lymphocyte Receptor for the Class IV Semaphorin CD100

Abstract

We have identified the lymphocyte semaphorin CD100/Sema4D as a CD40-inducible molecule by subtractive cDNA cloning. CD100 stimulation significantly enhanced the effects of CD40 on B cell responses. Administration of soluble CD100 markedly accelerated in vivo antigen-specific antibody responses. CD100 receptors with different binding affinities were detected on renal tubular cells (K(d) = approximately 1 x 10(-9)M) and lymphocytes (K(d) = approximately 3 x 10(-7)M). Expression cloning revealed that the CD100 receptor on lymphocytes is CD72, a negative regulator of B cell responsiveness. CD72 thus represents a novel class of semaphorin receptors. CD100 stimulation induced tyrosine dephosphorylation of CD72 and dissociation of SHP-1 from CD72. Our findings indicate that CD100 plays a critical role in immune responses by the novel mechanism of turning off negative signaling by CD72.

Regulation of immune cell responses by semaphorins and their receptors

“…49,50 Ligation of Sema4D to CD72 causes SHP1 to dissociate from CD72, resulting in B-cell and DC activation. 29 Consistent with this function, Sema4D-deficient mice exhibit impaired antibody production and priming of antigen-specific T cells. 46,47 In particular, Sema4D is crucially involved in T-cell-mediated neurological inflammatory diseases.…”

“…For example, Sema3E signals independently of NPs through plexin-D1, 16 while Sema7A uses integrins to exert its functions in both the nervous and immune systems. 27,28 In addition, two molecules unrelated to plexins and NPs, CD72 29 and T-cell immunoglobulin and mucin domaincontaining protein 2 (TIM-2), 30 functionally interact with Sema4D and Sema4A, respectively, in the immune system (Figure 1).…”

“…In the immune system, Sema4D is expressed in T cells, activated B cells and mature dendritic cells (DCs). 29,44,45 Sema4D promotes the activation of B cells and DCs to induce antibody production and antigen-specific T cells, respectively. 29,46,47 Plexin-B1 and CD72 were identified as the Sema4D receptors in the nervous and immune systems.…”

“…29,44,45 Sema4D promotes the activation of B cells and DCs to induce antibody production and antigen-specific T cells, respectively. 29,46,47 Plexin-B1 and CD72 were identified as the Sema4D receptors in the nervous and immune systems. 11,48 CD72 negatively regulates B cells by recruiting the tyrosine phosphatase Src homology phosphatase-1 (SHP1) to its immunoreceptor tyrosine-based inhibitory motifs (ITIM).…”

Roles of Sema4D–Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…The expression of Sema4D is abundantly observed in T cells, but only weakly detected in naive B cells, macrophages, and dendritic cells (DCs); however, its expression is significantly upregulated on cellular activation (12,13). Regarding its receptor systems, Sema4D has been shown to use two distinct receptors, plexin-B1 in the nervous system and CD72 in the immune system (11,14,15). We previously demonstrated the activation of B cells and DCs through the Sema4D-CD72 interactions (15,16); Sema4D-deficient mice display severe impairments in activation of B cells and DCs, resulting in impaired Ab production and Agspecific T cell priming (13,16).…”