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

描述（由申请人提供）：每年有近400万6个月以下的婴儿死于感染，其中许多是疫苗可预防的。婴儿的免疫系统不能像年龄较大的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机制来解释这种免疫力降低的婴儿：他们拥有先天性调节细胞，称为髓源性抑制细胞（MDSC），这是NK细胞和T细胞活化的有效抑制剂。MDSC以前从未在婴儿中描述过，在健康成人中也很少见。MDSC在成人癌症患者中得到了最好的表征，其中它们对抗肿瘤T细胞活性具有显著的抑制作用，尽管是可逆的。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细胞应答，导致生命早期对感染和疫苗接种的应答无效。本申请中提出的目的将在表型和功能上定义脐带血中的MDSC。我们将在婴儿出生后第一年进行纵向研究，以评估MDSC对婴儿对常规儿童疫苗和感染的免疫应答的影响。此外，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使用β-内酰胺酶-1抑制剂的β-内酰胺酶-1。最后，我们将确定抑制是否 MDSC功能的降低将消除它们的抑制作用并增强新生儿NK和T细胞活性。生命早期接种疫苗的挑战在于婴儿免疫应答的局限性。因此，阐明新生儿免疫力降低的机制以阐明增强婴儿免疫应答的方法是相关的。

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.