Newborn infants are highly susceptible to infection. This defect in host defence has generally been ascribed to the immaturity of neonatal immune cells; however, the degree of hyporesponsiveness is highly variable and depends on the stimulation conditions1–7. These discordant responses illustrate the need for a more unified explanation for why immunity is compromised in neonates. Here we show that physiologically enriched CD71+ erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after co-culture with neonatal splenocytes. Neonatal CD71+ cells express the enzyme arginase-2, and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with l-arginine overrides immunosuppression. In addition, the ablation of CD71+ cells in neonatal mice, or the decline in number of these cells as postnatal development progresses parallels the loss of suppression, and restored resistance to the perinatal pathogens Listeria monocytogenes and Escherichia coli8,9. However, CD71+ cell-mediated susceptibility to infection is counterbalanced by CD71+ cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition10,11.Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Thus, CD71+ cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. This finding challenges the idea that the susceptibility of neonates to infection reflects immune-cell-intrinsic defects and instead highlights processes that are developmentally more essential and inadvertently mitigate innate immune protection. We anticipate that these results will spark renewed investigation into the need for immunosuppression in neonates, as well as improved strategies for augmenting host defence in this vulnerable population.

Specific human leukocyte antigens (HLAs), notably HLA-B*27 and HLA-B*57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8+ T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B*27 or HLAB*57 allele groups do not. Here we show that CD8+ T cells restricted by 'protective' HLA allele groups are not suppressed by Tref cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8+ T cells to Tref cell–mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B*27– and HLA-B*57–restricted effectors also evade Tref cell–mediated suppression by directly killing Tref cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B*27 and HLA-B*57 allele groups are associated with delayed HIV-1 disease progression.

Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4 ؉ T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4 ؉ T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4 ؉ T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection. (Blood. 2012;119(18):4192-4204) IntroductionProphylactic interventions against HIV-1 acquisition, such as vaccine and microbicide candidates, have not proved efficacious or even enhanced acquisition in previous human clinical trials. 1,2 Even the most promising vaccine to date, which involved a canarypox prime followed by a gp120 protein boost, only showed limited efficacy that waned over time. 3 More effective strategies that block initial HIV-1 acquisition at the site of exposure are required. Interestingly, deletion of 32 base pairs in the ccr5 gene 4 and selective up-regulation of p21 in CD4 ϩ T cells from elite controllers 5 render some individuals naturally resistant to HIV-1 infection. The mechanism(s) responsible for resistance of CD4 ϩ T cells to HIV-1 infection are not well known, but defining them is vital for designing prophylactic interventions.Galectin-9 (Gal-9), a member of the ␤-galactoside-binding animal lectin family, was originally characterized as an eosinophil chemoattractant. 6 Subsequent studies determined that it is a versatile immunomodulator involved in a wide range of biologic activities, such as cell adhesion and migration, proliferation and apoptosis, interaction of host cells with microbial pathogens, regulatory T-cell (Treg) differentiation and function, dendritic cell (DC) maturation, and antimicrobial immunity. 7-13 Gal-9 is expressed by eosinophils, endothelial cells, T lymphocytes, DCs, macrophages, lymphoid cells, Kupffer cells, intestinal epithelial cells, and vascular endothelial cells. 10,[14][15][16][17][18][19] Wide distribution of Gal-9 on host cells demonstrates an important but complex role for this lectin, whose biologic effects are exerted by 2 receptors with distinct, and often opposing effects: TIM-3 (T-cell immunoglobulin [Ig] and mucin domain-containing molecule 3) 20 and cell surface protein disulfide isomerase...

The genetic factors associated with susceptibility or resistance to viral infections are likely to involve a sophisticated array of immune response. These genetic elements may modulate other biological factors that account for significant influence on the gene expression and/or protein function in the host. Among them, the role of the major histocompatibility complex in viral pathogenesis in particular human immunodeficiency virus (HIV) and hepatitis C virus (HCV), is very well documented. We, recently, added a novel insight into the field by identifying the molecular mechanism associated with the protective role of human leukocyte antigen (HLA)-B27/B57 CD8+ T cells in the context of HIV-1 infection and why these alleles act as a double-edged sword protecting against viral infections but predisposing the host to autoimmune diseases. The focus of this review will be reexamining the role of classical and non-classical HLA alleles, including class Ia (HLA-A, -B, -C), class Ib (HLA-E, -F, -G, -H), and class II (HLA-DR, -DQ, -DM, and -DP) in immune regulation and viral pathogenesis (e.g., HIV and HCV). To our knowledge, this is the very first review of its kind to comprehensively analyze the role of these molecules in immune regulation associated with chronic viral infections.

Newborns are highly susceptible to infection. The underlying mechanism of neonatal infection susceptibility has generally been associated with neonatal immune cell immaturity. In this study, we challenged this notion and built upon our recent discovery that neonates are physiologically enriched with erythroid TER119CD71 cells (Elahi et al. 2013. 504: 158-162). We have used, a common neonatal respiratory tract infection, as a proof of concept to investigate the role of these cells in newborns. We found that CD71 cells have distinctive immune-suppressive properties and suppress innate immune responses against infection. CD71 cell ablation unleashed innate immune response and restored resistance to infection. In contrast, adoptive transfer of neonatal CD71 cells into adult recipients impaired their innate immune response to infection. Enhanced innate immune response to was characterized by increased production of protective cytokines IFN-γ, TNF-α, and IL-12, as well as recruitment of NK cells, CD11b, and CD11c cells in the lung. Neonatal and human cord blood CD71 cells express arginase II, and this enzymatic activity inhibits phagocytosis of in vitro. Thus, our study challenges the notion that neonatal infection susceptibility is due to immune cell-intrinsic defects and instead highlights active immune suppression mediated by abundant CD71 cells in the newborn. Our findings provide additional support for the novel theme in neonatal immunology that immunosuppression is essential to dampen robust immune responses in the neonate. We anticipate that our results will spark renewed investigation in modulating the function of these cells and developing novel strategies for enhancing host defense to infections in newborns.