Hui Xu

Children and adults living with obesity have more severe influenza A virus (IAV) infection, but the underlying mechanisms are unclear. Natural killer (NK) cells play a key role in the innate immune responses to IAV and clearance of IAV-infected cells. ‘Trained immunity’ of NK cells (and other innate immune cells) refers to an initial stimulus (i.e. obesity) inducing metabolic and epigenetic changes that make these cells hyperinflammatory upon restimulation (i.e. with IAV). Here, we tested whether obesity in children induces trained immunity in NK cells. We have show that NK cells from children with obesity have a hyperinflammatory ‘trained’ phenotype, with increased expression of activation markers TLR2, CCR2, TLR4, HLA-DR and CD11b compared to children without obesity. Furthermore, we have demonstrate that NK cells from children with obesity have a heightened ex vivo IFN-γ response to stimulation with IAV (A/Auckland/4/2009, H1N1 and HKx31, H3N2) and epigenetic changes consistent trained immunity. A decrease in BMI z-score following weight-management was not associated with a reduction in the IFN-γ response, suggesting that weight loss is not sufficient to normalise NK cell function. Better understanding of obesity-related immune modulation is critical for development of new therapeutic strategies and improving outcomes in future IAV pandemics

The interaction between the CD4/CD8 co-receptors and LCK (an Src family tyrosine kinase) is thought to augment T cell activation upon recognition of peptide-loaded major histocompatibility complexes (pMHCs). How this interaction influences antigen-specific T cell development is unclear however, as is its impact on naïve and immune antigen-specific T cell repertoires. In mice expressing mutated endogenous LCK unable to bind co-receptors (LCK ^FREE mice), we show that influenza A virus (IAV)–derived pMHC-specific CD8 and CD4 T cell responses had a significantly narrowed T cell receptor (TCR) repertoire, favoring high-affinity TCRs. This narrowing was established during T cell development and was exacerbated after viral infection. The dissociation of LCK from co-receptors also resulted in the redirection of CD4-fated T cells to the CD8 lineage, with expanded pMHCII-specific cytotoxic CD8 T cells observed after IAV infection. Thus, LCK–co-receptor association is critical for ensuring T cell lineage fidelity and maximizing antigen-specific T cell repertoire diversity.

Antibodies forming a complex with antigen in vivo can dramatically change the antibody response to this antigen. In some situations, the response will be a 100‐fold stronger than in animals immunized with antigen alone and in other situations the response will be completely suppressed. IgG is known to suppress the antibody response, for example to erythrocytes, and this is used clinically in Rhesus prophylaxis. The mechanism behind IgG‐mediated immune suppression is still not understood. Here, we will review studies performed in experimental animal models and discuss the various hypotheses put forward to explain the profound suppressive effect of IgG. We conclude that an exclusive role for negative regulation of B cells through FcγRIIB, increased clearance of erythrocytes from the circulation, or complement‐mediated lysis, is unlikely. Epitope masking, where IgG hides the epitope from B cells, or trogocytosis, where IgG removes the epitope from the erythrocyte, are compatible with many observations. These two mechanisms are not mutually exclusive. Moreover, it cannot be ruled out that clearance, in combination with other mechanisms, plays a role.

The clinical sequelae associated with chronic HBV infection is generally regarded as a consequence of an inadequate and inappropriate immune response to active viral replication, predominantly at t...

Specific IgG antibodies, passively administered together with erythrocytes, suppress antibody responses against the erythrocytes. Although used to prevent alloimmunization in Rhesus (Rh)D-negative women carrying RhD-positive fetuses, the mechanism behind is not understood. In mice, IgG suppresses efficiently in the absence of Fcγ-receptors and complement, suggesting an Fc-independent mechanism. In line with this, suppression is frequently restricted to the epitopes to which IgG binds. However, suppression of responses against epitopes not recognized by IgG has also been observed thus arguing against Fc-independence. Here, we explored the possibility that non-epitope specific suppression can be explained by steric hindrance when the suppressive IgG binds to an epitope present at high density. Mice were transfused with IgG anti-4-hydroxy-3-nitrophenylacetyl (NP) together with NP-conjugated sheep red blood cells (SRBC) with high, intermediate, or low NP-density. Antibody titers and the number of single antibody-forming cells were determined. As a rule, IgG suppressed NP- but not SRBC-specific responses (epitope specific suppression). However, there was one exception: suppression of both IgM anti-SRBC and IgM anti-NP responses occurred when high density SRBC-NP was administered (non-epitope specific suppression). These findings answer a longstanding question in antibody feedback regulation and are compatible with the hypothesis that epitope masking explains IgG-mediated immune suppression.

Specific IgG, passively administered together with particulate antigen, can completely prevent induction of antibody responses to this antigen. The ability of IgG to suppress antibody responses to sheep red blood cells (SRBC) is intact in mice lacking FcγRs, C1q, C3, or complement receptors 1 and 2, suggesting that Fc-dependent effector functions are not involved. Two of the most widely discussed explanations for the suppressive effect are increased clearance of IgG-antigen complexes and/or that IgG "hides" the antigen from recognition by specific B cells, so-called epitope masking. The majority of data on how IgG induces suppression was obtained through studies of the effects on IgM-secreting single spleen cells during the first week after immunization. Here, we show that IgG also suppresses antigen-specific extra-follicular antibody-secreting cells, germinal center B-cells, long-lived plasma cells, long-term IgG responses and induction of memory antibody responses. IgG anti-SRBC reduced the amount of SRBC in the spleens of wild-type but not of FcγR-deficient mice. However, no correlation between suppression and the amount of SRBC in the spleen was observed, suggesting that increased clearance does not explain IgG-mediated suppression. Instead we found compelling evidence for epitope masking because IgG anti-NP administered with NP-SRBC suppressed the IgG anti-NP but not the IgG anti-SRBC response. Vice versa, IgG anti-SRBC administered with NP-SRBC, suppressed only the IgG anti-SRBC response. In conclusion, passively transferred IgG suppressed all measured parameters of an antigen-specific antibody/B cell response and an important mechanism of action is likely to be epitope masking.

IgE, forming an immune complex with small proteins, can enhance the specific antibody and CD4⁺ T cell responses in vivo. The effects require the presence of CD23 (Fcε-receptor II)⁺ B cells, which capture IgE-complexed antigens (Ag) in the circulation and transport them to splenic B cell follicles. In addition, also CD11c⁺ cells, which do not express CD23, are required for IgE-mediated enhancement of T cell responses. This suggests that some type of dendritic cell obtains IgE-Ag complexes from B cells and presents antigenic peptides to T cells. To elucidate the nature of this dendritic cell, mice were immunized with ovalbumin (OVA)-specific IgE and OVA and different populations of CD11c⁺ cells, obtained from the spleens four hours after immunization, were tested for their ability to present OVA. CD8α⁻ conventional dendritic cells (cDCs) were much more efficient in inducing specific CD4⁺ T cell proliferation ex vivo than were CD8α⁺ cDCs or plasmacytoid dendritic cells. Thus, IgE-Ag complexes administered intravenously are rapidly transported to the spleen by recirculating B cells where they are delivered to CD8α⁻ cDCs which induce proliferation of CD4⁺ T cells.

IgE–antigen complexes, administered intravenously to mice, induce a several 100‐fold higher specific antibody response than antigen alone. Additionally, in vivo activation and proliferation of specific CD4⁺ T cells is enhanced. The mechanism behind these effects is thought to be that peripheral B cells capture IgE–antigen complexes via their low‐affinity receptor for IgE, CD23, and rapidly transport them to splenic B cell follicles where an immune response is initiated. Here, we demonstrate that ovalbumin, covalently coupled to anti‐CD23 antibodies and administered intravenously to mice, is also transported to splenic follicles and induces an enhanced primary antibody response. These effects are absent in CD23‐deficient mice. No enhanced induction of immunological memory was observed. These findings extend previous observations regarding the in vivo role of CD23 and emphasize that recirculating B cells play an important role in antigen transport to the spleen.