Myeloid derived suppressor cells are present at high frequency in neonates and suppress in vitro T cell responses

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

Evidence for Female-Biased Dispersal in the Protandrous Hermaphroditic Asian Seabass, Lates calcarifer

Movement of individuals influences individual reproductive success, fitness, genetic diversity and relationships among individuals within populations and gene exchange among populations. Competition between males or females for mating opportunities and/or local resources predicts a female bias in taxa with monogamous mating systems and a male-biased dispersal in polygynous species. In birds and mammals, the patterns of dispersal between sexes are well explored, while dispersal patterns in protandrous hermaphroditic fish species have not been studied. We collected 549 adult individuals of Asian seabass (Lates calcarifer) from four locations in the South China Sea. To assess the difference in patterns of dispersal between sexes, we genotyped all individuals with 18 microsatellites. Significant genetic differentiation was detected among and within sampling locations. The parameters of population structure (FST), relatedness (r) and the mean assignment index (mAIC), in combination with data on tagging-recapture, supplied strong evidences for female-biased dispersal in the Asian seabass. This result contradicts our initial hypothesis of no sex difference in dispersal. We suggest that inbreeding avoidance of females, female mate choice under the condition of low mate competition among males, and male resource competition create a female-biased dispersal. The bigger body size of females may be a cause of the female-biased movement. Studies of dispersal using data from DNA markers and tagging-recapture in hermaphroditic fish species could enhance our understanding of patterns of dispersal in fish

Effect of G-MDSC on IFN-gamma production.

<p>(<b>A</b>) Cord blood CD3^pos T cells and adult CD3^pos CD45RO^neg T cells were assessed for IFN-gamma production by ELISpot after anti-CD3/CD28 bead stimulation (n = 11 independent experiments performed in triplicate for neonates and 9 independent experiments for adults). Statistical significance determined by the Mann Whitney test. (<b>B</b>) Neonatal G-MDSC decrease IFN-gamma production after anti-CD3/CD28 bead stimulation. (n = 13 independent experiments performed in triplicate). (<b>C</b>) G-MDSC frequency correlation with suppression T cell of IFN-gamma production by G-MDSC. G-MDSC frequencies were correlated to suppression using the Spearman rank correlation test (n = 11 independent experiments).</p

Effect of neonatal G-MDSC on T cell proliferation.

<p>(<b>A</b>) Proliferative responses of purified T cells in the presence or absence of G-MDSC after anti-CD3/CD28 bead stimulation (n = 28 independent experiments performed in duplicate for CD3 plots, n = 6 for CD4 and CD8 plots). Significance determined by the Wilcoxon Matched-Pair Signed Rank test. (<b>B</b>) Proliferative responses of purified adult naïve T cells (n = 9 independent experiments performed in duplicate) compared to cord blood T cells (n = 28 independent experiments performed in duplicate) after anti-CD3/CD28 bead stimulation. Statistical significance determined by the Mann Whitney test. (<b>C</b>) Suppression of T cell proliferation by autologous G-MDSC titration. (n = 4 independent experiments performed in duplicate). (<b>D</b>) Suppression of T cell proliferative responses by G-MDSC is contact dependent. (n = 5 independent experiments performed in duplicate). (<b>E</b>) G-MDSC frequency correlates with suppression of T cell proliferation by G-MDSC. G-MDSC frequencies were correlated to suppression of T cell proliferation by G-MDSC using the Spearman rank correlation test (n = 16 independent experiments).</p

Characterization and longitudinal analysis of MDSC populations in cord blood, infants and adults.

<p>(<b>A</b>) Gating strategy and identification of HLA-DR/CD14^neg, CD33/CD11b/CD15^pos G-MDSC in adult and cord blood. Further characterization of HLA-DR/CD14^neg, CD33/CD11b/CD15^pos cells by intracellular staining of Arginase I. (<b>B</b>) Frequency of HLA-DR/CD14^neg, CD33/CD11b/CD15^pos cells of: (i) CBMC isolated from CB collected from healthy pregnancies in Seattle, WA (n = 25); (ii) PBMC isolated from neonates in Cape Town, South Africa at 6-weeks of age (n = 9); (iii) PBMC isolated from 6–24 month-old infants in Seattle, WA (n = 29); (iv) and PBMC isolated from healthy adults in Seattle, WA (n = 28). Statistical significance determined by the Mann Whitney test. (<b>C</b>) Wright-Giemsa cytospin of CB samples and phenotype determination by clinical pathology of neutrophils and G-MDSC (Average, n = 2 independent experiments). Magnification 600X. (<b>D</b>) Proportions of neutrophils at various stages of development in the neutrophil and the G-MDSC fractions.</p