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T-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies are boosted in children with current infection, and are higher in females. The children with the very highest antibody levels have increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria.

Morbidity and mortality rates from seasonal and pandemic influenza occur disproportionately in high-risk groups, including Indigenous people globally. Although vaccination against influenza is recommended for those most at risk, studies on immune responses elicited by seasonal vaccines in Indigenous populations are largely missing, with no data available for Indigenous Australians and only one report published on antibody responses in Indigenous Canadians. We recruited 78 Indigenous and 84 non-Indigenous Australians vaccinated with the quadrivalent influenza vaccine into the Looking into InFluenza T cell immunity - Vaccination cohort study and collected blood to define baseline, early (day 7), and memory (day 28) immune responses. We performed in-depth analyses of T and B cell activation, formation of memory B cells, and antibody profiles and investigated host factors that could contribute to vaccine responses. We found activation profiles of circulating T follicular helper type-1 cells at the early stage correlated strongly with the total change in antibody titers induced by vaccination. Formation of influenza-specific hemagglutinin-binding memory B cells was significantly higher in seroconverters compared with nonseroconverters. In-depth antibody characterization revealed a reduction in immunoglobulin G3 before and after vaccination in the Indigenous Australian population, potentially linked to the increased frequency of the G3m21* allotype. Overall, our data provide evidence that Indigenous populations elicit robust, broad, and prototypical immune responses following immunization with seasonal inactivated influenza vaccines. Our work strongly supports the recommendation of influenza vaccination to protect Indigenous populations from severe seasonal influenza virus infections and their subsequent complications. [ABSTRACT FROM AUTHOR]

Background: RTS,S is the leading malaria vaccine candidate but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection; however, it is unclear how these protective antibodies function.Methods: We quantified the induction of functional anti-CSP antibody responses in healthy malaria-naive adults (N = 45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fcγ-receptors (FcγRs) that are expressed on immune cells, which promote various immunological functions.Results: Our major findings were (1) RTS,S-induced antibodies mediated Fc-dependent effector functions, (2) functional antibodies were generally highest after the second vaccine dose, (3) functional antibodies targeted multiple regions of CSP, (4) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (P < .05), and (5) nonprotected subjects had higher levels of anti-CSP IgM.Conclusions: Our data suggest a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines.Clinical Trials Registration: NCT00075049. [ABSTRACT FROM AUTHOR]

HIV-1 infection is transmitted primarily by sexual exposure, with semen being the principal contaminated fluid. However, HIV-specific immune response in semen has been understudied. We investigated specific parameters of the innate, cellular, and humoral immune response that may affect semen infectivity in macaques infected with SIVmac251. Serial semen levels of cytokines and chemokines, SIV-specific antibodies, neutralization, and FcγR-mediated functions and SIV-specific T-cell responses were assessed and compared to systemic responses across 53 cynomolgus macaques. SIV infection induced an overall inflammatory state in the semen. Several pro-inflammatory molecules correlated with SIV virus levels. Effector CD8+ T cells were expanded in semen upon infection. SIV-specific CD8+ T-cells that expressed multiple effector molecules (IFN-γ+MIP-1β+TNF+/−) were induced in the semen of a subset of SIV-infected macaques, but this did not correlate with local viral control. SIV-specific IgG, commonly capable of engaging the FcγRIIIa receptor, was detected in most semen samples although this positively correlated with seminal viral load. Several inflammatory immune responses in semen develop in the context of higher levels of SIV seminal plasma viremia. These inflammatory immune responses could play a role in viral transmission and should be considered in the development of preventive and prophylactic vaccines. [ABSTRACT FROM AUTHOR]

Background: With more than 600,000 deaths from malaria, mainly of children under five years old and caused by infection with Plasmodium falciparum, comes an urgent need for an effective anti-malaria vaccine. Limited details on the mechanisms of protective immunity are a barrier to vaccine development. Antibodies play an important role in immunity to malaria and monocytes are key effectors in antibody-mediated protection by phagocytosing antibody-opsonised infected erythrocytes (IE). Eliciting antibodies that enhance phagocytosis of IE is therefore an important potential component of an effective vaccine, requiring robust assays to determine the ability of elicited antibodies to stimulate this in vivo. The mechanisms by which monocytes ingest IE and the nature of the monocytes which do so are unknown. Methods: Purified trophozoite-stage P. falciparum IE were stained with ethidium bromide, opsonised with antierythrocyte antibodies and incubated with fresh whole blood. Phagocytosis of IE and TNF production by individual monocyte subsets was measured by flow cytometry. Ingestion of IE was confirmed by imaging flow cytometry. Results: CD14hiCD16+ monocytes phagocytosed antibody-opsonised IE and produced TNF more efficiently than CD14hiCD16- and CD14loCD16+ monocytes. Blocking experiments showed that Fcγ receptor IIIa (CD16) but not Fcγ receptor IIa (CD32a) or Fcγ receptor I (CD64) was necessary for phagocytosis. CD14hiCD16+ monocytes ingested antibody-opsonised IE when peripheral blood mononuclear cells were reconstituted with autologous serum but not heat-inactivated autologous serum. Antibody-opsonised IE were rapidly opsonised with complement component C3 in serum (t1/2 = 2-3 minutes) and phagocytosis of antibody-opsonised IE was inhibited in a dose-dependent manner by an inhibitor of C3 activation, compstatin. Compared to other monocyte subsets, CD14hiCD16+ monocytes expressed the highest levels of complement receptor 4 (CD11c) and activated complement receptor 3 (CD11b) subunits. Conclusions: We show a special role for CD14hiCD16+ monocytes in phagocytosing opsonised P. falciparum IE and production of TNF. While ingestion was mediated by Fcγ receptor IIIa, this receptor was not sufficient to allow phagocytosis; despite opsonisation with antibody, phagocytosis of IE also required complement opsonisation. Assays which measure the ability of vaccines to elicit a protective antibody response to P. falciparum should consider their ability to promote phagocytosis and fix complement. [ABSTRACT FROM AUTHOR]

The varied interaction of the Fc region of IgA with receptors confers this antibody class with many of its unique properties. The epithelial polymeric Ig receptor on mucosal epithelial cells transports polymeric immunoglobulin A (pIgA) produced by mucosal B cells to the mucosal surface where, in complex with the secretory component (SC), this secretory immunoglobulin A (SIgA) excludes the multitude of dietary, environmental, and microbial antigens that continuously bombard the mucosae. In health, this IgA-mediated exclusion not only forms the initial defence against infection, it also spares the systemic immune system from potentially deleterious responses to innocuous antigens which can otherwise culminate in inflammatory bowel disease or asthma. Beyond antigen exclusion, in closer encounters with antigens, IgA receptors play roles in protective immunity and disease. FcaRI is the principal myeloid IgA receptor and is responsible for differing IgA-mediated effector responses such as respiratory burst, degranulation, and phagocytosis variously by granulyoctes, monocytes, and macrophages. Furthermore an unknown IgA receptor specific for the secretory component (SC) elicits powerful effector responses from eosinophils. On dendritic cells, FcaRI participates in antigen presentation while on microfold cells, key cells in mucosal antigen presentation, another unknown IgA receptor functions in the transport of antigens across the mucosal epithelial barrier. The activity of another uncharacterized IgA1/IgD receptor on T cells may affect autoimmune disorders. The interplay of different IgA receptors affects immune complex deposition in the common renal disease immunoglobulin A nephropathy (IgAN). Finally, the therapeutic application of various IgA receptors has been sought in the areas of infectious disease, vaccines, and cancer. [ABSTRACT FROM AUTHOR]

Abstract: The majority of human subjects who receive subcutaneous allergen immunotherapy (IT) develop decreased sensitivity to their allergens. Multiple factors may explain the efficacy of IT, some evidence support a role for allergen specific IgG antibodies. There is controversy whether such antibodies act by blocking allergen binding to IgE or initiation of active inhibitory signaling through low affinity IgG receptors (FcγRIIB) on mast cells and basophils. In this study, we addressed this question using peripheral blood from cat non-allergic, cat allergic, and immunotherapy-treated cat allergic subjects. Blood from subjects who received IT contain IgG antibodies that mediate inhibition of basophil activation by a mechanism that is blocked by antibodies specific for the inhibitory IgG receptor FcγRIIB. Surprisingly, inhibition was also blocked by aglycosylated, putatively non-FcR binding, antibodies that are specific for the FcγRIIA, suggesting a contribution of this receptor to the observed effect. Consistent with a cooperative effect, ex vivo basophils were found to express both IgG receptors. In other studies we found that basophils from subjects who were both chronically exposed to allergen and were producing both cat allergen specific IgE and IgG, are hyporesponsive to allergen. These studies confirm that IgG antibodies produced during IT act primarily by stimulation of inhibitory signaling, and suggest that FcγRIIA and FcγRIIB function cooperatively in activation of inhibitory signaling circuit. We suggest that under normal physiologic conditions in which only a small proportion of FcɛRI are occupied by IgE of a single allergen specificity, FcγRIIA co-aggregation may, by providing activated Lyn, be required to fuel activation of inhibitory FcγRIIB function. [Copyright &y& Elsevier]