Low-Level Expression of CD138 Marks Naturally Arising Anergic B Cells.

Autoreactive B cells are not entirely deleted, but some remain as immunocompetent or anergic B cells. Although the persistence of autoreactive B cells as anergic cells has been shown in transgenic mouse models with the expression of B cell receptor (BCR) reactive to engineered self-antigen, the characterization of naturally occurring anergic B cells is important to identify them and understand their contribution to immune regulation or autoimmune diseases. We report here that a low-level expression of CD138 in the splenic B cells marks naturally arising anergic B cells, not plasma cells. The CD138int B cells consisted of IgMlowIgDhigh follicular (FO) B cells and transitional 3 B cells in homeostatic conditions. The CD138int FO B cells showed an anergic gene expression profile shared with that of monoclonal anergic B cells expressing engineered BCRs and the gene expression profile was different from those of plasma cells, age-associated B cells, or germinal center B cells. The anergic state of the CD138int FO B cells was confirmed by attenuated Ca2+ response and failure to upregulate CD69 upon BCR engagement with anti-IgM, anti-IgD, anti-Igκ, or anti-IgG. The BCR repertoire of the CD138int FO B cells was distinct from that of the CD138- FO B cells and included some class-switched B cells with low-level somatic mutations. These findings demonstrate the presence of polyclonal anergic B cells in the normal mice that are characterized by low-level expression of CD138, IgM downregulation, reduced Ca2+ and CD69 responses upon BCR engagement, and distinct BCR repertoire.

Mechanism of oral tolerance / 国际儿科学杂志

Oral tolerance is a state of no or low response to a specific oral antigen,but there are still normal immune responses to other antigens.Anaphylaxis may occur when oral tolerance is not established or destroyed.In recent years,the incidence of food allergy in Chinese children has increased,with an average of 5.83 ％ reported by parents.Therefore,it is of great significance to explore the mechanisms of oral tolerance.The mechanisms of oral tolerance include active suppression,bypass suppression,clonal anergy/deletion.Oral administration of low-dose antigen can induce regulatory T cells to secrete inhibitory cytokines and actively inhibit effector T cells.Oral administration of high-dose antigen can induce clonal anergy/deletion.Regulatory B cells,dendritic cells,various cytokines,gut microbiota and short-chain fatty acids also play an important role in oral tolerance.This review focuses on the mechanism and some influencing factors of oral tolerance.

Staphylococcal Enterotoxin B (SEB) Induces Memory CD4 T Cell Anergy in vivo and Impairs Recall Immunity to Unrelated Antigens.

INTRODUCTION: Naïve and memory T cells can utilize unique regulatory pathways to promote protection but prevent self-reactivity. A bacterial superantigen SEB exploits unique TCR proximal signaling processes in memory CD4 T cells to induce clonal anergy. The aim of this study was to determine if SEB could antagonize memory CD4 T cells in vivo and whether there would be consequences on recall immune responses. We evaluated Ab responses to a T-dependent antigen as a measurement of memory T cell helper function. METHOD: BALB/c mice were primed with TNP-RGG to elicit memory B cells and also immunized with an ovalbumin peptide to elicit memory helper T cells. Another group of TNP-RGG immunized mice were used as adoptive transfer recipients of exogenous DO11.10 memory T cells. Mice were challenged with TNP-OVA with or without prior administration of SEB. B cells secreting IgM or IgG TNP-specific Ab were enumerated by ELISPOT as indicators of primary versus secondary humoral immunity. RESULTS: Comparing the SEB and non-SEB-treated groups, the SEB-treated group failed to produce TNP-specific IgG in response to challenge with TNP-OVA, even if they were previously immunized with OVA. All groups produced IgM, indicating that the primary Ab responses and naïve helper T cells were not impacted by SEB. SEB had no negative impact when DO11.10 × Fyn-/- memory T cells were used as donor cells. CONCLUSION: The present study indicated that SEB selectively targeted memory CD4 T cells in vivo and prevented helper function. Consequently, recall humoral immunity was lost. The data are most consistent with in vivo T cell anergy as opposed to indirect suppression as elimination of Fyn kinase restored helper function. These data suggest that bacterial superantigens can impair post-vaccination memory cell responses to unrelated antigens via their ability to target Vb families and antagonize memory cell activation.

Maintenance of CD8+T-cell anergy by CD4+CD25+ regulatory T cells in chronic graft-versus-host disease

In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8+T cells rapidly fall into anergy to host cells, while donor CD4+T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8+T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8+T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4+CD25+regulatory T cells (T(reg) cells) are critical in maintaining the donor CD8+T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of T(reg) cells in determining cGVHD versus aGVHD.

The Effects of Maturation Resistant Donor Dendritic Cells on Alloimmune Response in Mice / 대한신장학회잡지

BACKGROUND: Although dendritic cells (DCs) are the most influential antigen presenting cells maturation of DC is the critical control point toward either activation or regulation of immunity. We hypothesized that pretreatment with donor DCs, if which were maturation-resistant in vivo, could enhance engraftment by inducing inactivated state for allo- reactive T cell clones. METHODS: Immature DCs were prepared by 6- day culture of BM cells and we used paraformaldehyde for locking the DCs as immature phenotypes. We did in vitro and in vivo MLR to evaluate the effect of maturation resistant DCs on alloreactive T cells and we confirmed the effect of DCs in MHC full mismatched skin and islet transplantation model. RESULTS: Fixed DCs in immature state were resistant to maturation stimuli and weak stimulator for allo-reactive T cells (CB6F1-->C3H). In contrast, fixed DCs in mature state stimulated allogeneic T cell proliferation effectively. Splenocytes isolated from mice 2 weeks after maturation resistant DC injection could not be reactivated and maintained naive phenotype when cocultured with allogeneic splenocytes (BALB/c-->C57BL6). Consistent with this finding maturation resistant DC treatment suppressed MLR-driven T cell division (CB6F1-->C3H) as assessed by CFSE analysis. But, CD25+ T cells depletion by treatment with anti-CD25 prior to DCs transfer attenuated this regulatory effect of DCs. In a MHC mismatched transplantation model (CB6F1-->C3H), treatment with maturation-resistant DCs 2 weeks before operation, markedly prolonged skin and islet graft survival. But C3H mice pretreated with CB6F1 DCs rejected DBA1 (H-2q) skin graft within 14 days. CONCLUSION: These findings suggest the maintenance of immaturity of DCs is a key factor in modulating alloimmune responses through dendritic cells.