LeIF, a gene homologue of the eukaryotic initiation factor 4A was first described as a leishmanial antigen that induced a Th1-type T cell response in peripheral blood mononuclear cells (PBMC) from leishmaniasis patients. Moreover, the interferon (IFN)-gamma production by PBMC was found to be interleukin (IL)-12 dependent. Herein, we characterize the effects of LeIF on cytokine production and expression of surface molecules by normal human monocytes as well as by monocyte-derived macrophages and dendritic cells (MoDC). LeIF was a strong inducer of IL-12 and, to a lesser extent, of IL-10 and tumor necrosis factor (TNF)-alpha in macrophages and MoDC. IL-12 production did not require CD40 triggering, confirming that the ability of LeIF to induce IL-12 was not mediated through an effect on T cells. However, addition of soluble CD40 ligand (L) synergistically augmented IL-12 production in macrophages and MoDC. The cytokine-inducing activity of LeIF is located in the N-terminal portion of the molecule and was both proteinase K sensitive and polymyxin B resistant. LeIF, lipopolysaccharide and fixed Staphylococcus aureus all induced comparable amounts of IL-12, validating the potent cytokine-inducing effects of LeIF. Moreover, of these stimuli, LeIF had the highest IL-12/IL-10 and IL-12/TNF-alpha ratio demonstrating the preference of LeIF for IL-12 induction. Studies investigating the expression of surface molecules showed that LeIF up-regulated B7-1 and CD54 (ICAM-1) on macrophages and MoDC. To our knowledge this is the first report describing IL-12 production, up-regulation of co-stimulatory and intercellular adhesion molecules by monocytic antigen-presenting cells in response to a protein from a pathogenic microorganism. These immunomodulatory characteristics of LeIF might be excellent properties for a Th1-type adjuvant.
Over 4 million infants die each year from infections, many of which are vaccine-preventable. Young infants respond relatively poorly to many infections and vaccines, but the basis of reduced immunity in infants is ill defined. We sought to investigate whether myeloid-derived suppressor cells (MDSC) represent one potential impediment to protective immunity in early life, which may help inform strategies for effective vaccination prior to pathogen exposure. We enrolled healthy neonates and children in the first 2 years of life along with healthy adult controls to examine the frequency and function of MDSC, a cell population able to potently suppress T cell responses. We found that MDSC, which are rarely seen in healthy adults, are present in high numbers in neonates and their frequency rapidly decreases during the first months of life. We determined that these neonatal MDSC are of granulocytic origin (G-MDSC), and suppress both CD4+ and CD8+ T cell proliferative responses in a contact-dependent manner and gamma interferon production. Understanding the role G-MDSC play in infant immunity could improve vaccine responsiveness in newborns and reduce mortality due to early-life infections.
The fate of protective immunity following mild severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection remains ill defined. Here, we characterize antibody responses in a cohort of participants recovered from mild SARS-CoV-2 infection with follow-up to 6 months. We measure immunoglobulin A (IgA), IgM, and IgG binding and avidity to viral antigens and assess neutralizing antibody responses over time. Furthermore, we correlate the effect of fever, gender, age, and time since symptom onset with antibody responses. We observe that total anti-S trimer, anti-receptor-binding domain (RBD), and anti-nucleocapsid protein (NP) IgG are relatively stable over 6 months of follow-up, that anti-S and anti-RBD avidity increases over time, and that fever is associated with higher levels of antibodies. However, neutralizing antibody responses rapidly decay and are strongly associated with declines in IgM levels. Thus, while total antibody against SARS-CoV-2 may persist, functional antibody, particularly IgM, is rapidly lost. These observations have implications for the duration of protective immunity following mild SARS-CoV-2 infection.
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of granulocytic or monocytic cells that suppress innate as well as adaptive immune responses. In healthy adults, immature myeloid cells differentiate into macrophages, dendritic cells, and granulocytes in the bone marrow and MDSC are rarely detected in peripheral blood. However, in certain pathologies, in particular malignancies and chronic infection, differentiation of these cells is altered resulting in accumulation of circulating suppressive myeloid cells. MDSC express suppressive factors such as arginase-1, reactive oxygen species, and inducible nitric oxide synthase, which have the ability to inhibit T cell proliferation and cytoxicity, induce the expansion of regulatory T cells, and block natural killer cell activation. It is increasingly recognized that MDSC alter the immune response to several cancers, and perhaps chronic viral infections, in clinically important ways. In this review, we outline the potential contribution of MDSC to the generation of feto-maternal tolerance and to the ineffective immune responses to many infections and vaccines observed in early post-natal life. Granulocytic MDSC are present in large numbers in pregnant women and in cord blood, and wane rapidly during infancy. Furthermore, cord blood MDSC suppress in vitro T cell and NK responses, suggesting that they may play a significant role in human immune ontogeny. However, there are currently no data that demonstrate in vivo effects of MDSC on feto-maternal tolerance or immune ontogeny. Studies are ongoing to evaluate the functional importance of MDSC, including their effects on control of infection and response to vaccination in infancy. Importantly, several pharmacologic interventions have the potential to reverse MDSC function. Understanding the role of MDSC in infant ontogeny and their mechanisms of action could lead to interventions that reduce mortality due to early-life infections.
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