CD47 Expression on T Cell Is a Self-Control Negative Regulator of Type 1 Immune Response

Abstract

The cytokine milieu and dendritic cells (DCs) direct Th1 development. Yet, the control of Th1 polarization by T cell surface molecules remains ill-defined. We here report that CD47 expression on T cells serves as a self-control mechanism to negatively regulate type 1 cellular and humoral immune responses in vivo. Th2-prone BALB/c mice that lack CD47 (CD47−/−) displayed a Th1-biased Ab profile at steady state and after immunization with soluble Ag. CD47−/− mice mounted a T cell-mediated exacerbated and sustained contact hypersensitivity (CHS) response. After their adoptive transfer to naive CD47-deficient hosts 1 day before immunization with soluble Ag, CD47−/− as compared with CD47+/+CD4+ transgenic (Tg) T cells promoted the deviation of Ag-specific T cell responses toward Th1 that were characterized by a high IFN-γ:IL-4 cytokine ratio. Although selective CD47 deficiency on DCs led to increased IL-12p70 production, CD47−/−Tg T cells produced more IFN-γ and displayed higher T-bet expression than CD47+/+ Tg T cells in response to OVA-loaded CD47−/− DCs. CD47 as part of the host environment has no major contribution to the Th1 polarization responses. We thus identify the CD47 molecule as a T cell-negative regulator of type 1 responses that may limit unwanted collateral damage to maximize protection and minimize host injury.

CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

“…Consistent with this active immunization and protection, naive CD47KO mice were found to induce higher levels of virus-specific IgG antibodies and to be more effectively protected after viral infection compared to WT mice. Thus, these results suggest that CD47 negatively modulates protective immune responses, which is consistent with previous findings (22).…”

“…It has been shown that DCs and the cytokine milieu influence a Th1 immune response. Consistent with the Th1 type IgG isotype responses in this study, a previous study demonstrated that CD47 deficiency enhanced a Th1 dominant cell response, producing IFN-␥ and a Th1-biased antibody response (22), implying that CD47 is a negative regulator of the Th1 immune response. Thus, we expected that vaccination with VLPs might promote an enhanced Th1 dominant response and in turn induce a high ratio of IgG2c isotype antibody, although similar numbers of antigen-specific CD4 ϩ and CD8 ϩ T cells were observed in the lungs of nonimmune WT and CD47KO mice, as well as in immune WT and CD47KO mice.…”

CD47high Expression on CD4 Effectors Identifies Functional Long-Lived Memory T Cell Progenitors

“…2F), indicating that survivors of the contraction phase have converted to CD47 high cells. Notably, CD47 2/2 Tg T cells transferred into CD47 2/2 mice displayed an effector, rather than T CM phenotype, at this later time point, supporting the concept that enhanced cell survival, T-bet expression, and Th1 responses as seen in CD47-deficient mice (13,21) correlate with impaired CD4 T CM differentiation.…”

“…Also, equal proportions of the two memory CD4 T cell subsets are generated after Listeria monocytogenes infection in WT mice: the T-bet high cells that lack CCR7 and rapidly produce IFN-g, and thus resemble Th1 effector memory cells; and the T-bet low cells that express CCR7 and produce none of the lineage-defining cytokines, and therefore resemble T CM (25,31). Lack of CD47 expression enhances T-bet expression on CD4 T cells as well as exacerbates and sustains T cell-mediated contact hypersensitivity response, which correlates with an enhanced type 1 IR (13,32). Therefore, the lower frequency of T CM seen in CD47 2/2 hosts in the absence of lymphosplenomegaly may be best explained by increased T-bet combined with decreased production of IL-7 in CD47 2/2 when compared with WT hosts (33).…”

“…CD47 interacts with two ligands, signal regulatory protein a and thrombospondin-1. Thrombospondin-1/CD47 interactions inhibit IL-12 production by DCs (10,11), IL-12 responsiveness (12), and Th1 differentiation (13,14), whereas it promotes the differentiation of regulatory T cells under neutral conditions (15,16). Because inflammatory context negatively regulates memory T cell development (17), CD47 may control the generation of memory T cells.…”