Myeloid-derived Suppressor cells (MDSC) suppress infant immune responses

描述（由申请人提供）：每年约有400万6个月以下的婴儿死于感染，其中许多是可以通过疫苗预防的。婴儿免疫系统不能像大龄儿童或成人那样有效地控制感染或对疫苗接种作出反应，这归因于免疫不成熟。在这里，我们已经确定了一种解释婴儿免疫力下降的机制：他们拥有先天调节细胞，称为髓源性抑制细胞（MDSC），它是NK细胞和T细胞活化的有效抑制剂。MDSC以前从未在婴儿中被描述过，在健康成人中也很少见到。MDSC在成年癌症患者中具有显著的（尽管是可逆的）抑制抗肿瘤T细胞活性的作用。我们的总体假设是，新生儿和婴儿中存在的MDSC群体抑制婴儿NK和T细胞反应，导致生命早期对感染和疫苗接种的反应效率低下。本应用的目的将在表型和功能上定义脐带血中的MDSC。我们将对出生第一年的婴儿进行纵向研究，以评估MDSC对婴儿对常规儿童疫苗和感染的免疫反应的影响。此外，研究目的将确定MDSC对新生儿NK细胞和T细胞的抑制是否依赖于精氨酸酶-1抑制剂的使用。最后我们将确定是否有抑制作用

DESCRIPTION (provided by applicant): Almost 4 million infants under 6 months old die each year of infections, many of which are vaccine-preventable. The infant immune system cannot control infection, or respond to vaccination, as effectively as older children's or adults', which has been attributed to immunologic immaturity. Here, we have identified a mechanism to explain this reduced immunity in young infants: they possess innate regulatory cells, called myeloid-derived suppressor cells (MDSC), which are potent inhibitors of both NK cell and T cell activation. MDSC have never been described before in infants, and are rarely seen in healthy adults. MDSC have best been characterized in adult cancer patients where they have remarkable, albeit reversible, suppressive effects on anti-tumor T cell activity. Our overall hypothesis is that MDSC populations present in neonates and infants suppress infant NK and T cell responses resulting in inefficient responses to both infection and vaccination early in life. The aims addressed in this application will phenotypically and functionally define MDSC in cord blood. We will perform longitudinal studies in infants during the first year of life to assess the influence of MDSC on infant immune responses to routine childhood vaccines and infections. In addition, the aims will determine if suppression of neonatal NK and T cells by MDSC is arginase-1-dependent with the use of arginase-1 inhibitors. Finally we will determine if inhibition of MDSC function will abrogate their suppressive actions and enhance neonatal NK and T cell activity. The challenge of early life vaccination lies in the limitations of the infant immune response. Thus, it is pertinent to elucidate the mechanisms behind reduced neonatal immunity to illuminate ways to enhance infant immune responses.