The Role of CD5 In Dendritic Cell Mediated Immune Suppression

描述（由申请人提供）：免疫系统不应对自身抗原（耐受性）作出反应，但会识别并消除非自身抗原（免疫性）。然而，免疫系统对非自身抗原的过度反应可引起称为超敏反应的疾病。接触性超敏反应（contact hypersensitivity，CHS）是一种由T细胞介导的对皮肤半抗原的迟发型超敏反应。树突状细胞（DC）是诱导CHS应答的主要抗原呈递细胞。然而，对DC介导的免疫应答抑制机制知之甚少。CD 5是由T细胞和DC表达的表面分子。众所周知，CD 5介导T细胞的抑制信号，在免疫耐受中起重要作用。然而，它是未探索的DC上表达的CD 5是否具有DC介导的免疫调节的作用。我们的初步研究表明，CD 11 c+髓样和淋巴样DC表达CD 5从脾，淋巴结和胸腺，而它是在浆细胞样DC检测不到。从CD 5基因敲除（CD 5-/-）小鼠转移半抗原标记的CD 11 c + DC诱导比野生型DC显著更高水平的CHS应答。相应地，来自CD 5-/- DC致敏小鼠的半抗原致敏的T细胞比来自野生型DC致敏动物的那些产生更高水平的炎性细胞因子。进一步的实验表明，CD 5-/- DC比野生型DC更有效地激活CD 4+和CD 8 + T细胞并诱导抗肿瘤免疫。这些数据首次证明了DC上表达的CD 5分子在T细胞活化和诱导免疫应答中对DC功能具有抑制作用。本申请的假设是DC和T细胞之间的CD 5-CD 5相互作用抑制T细胞活化，并且是DC诱导的免疫抑制的重要机制。提出了三个具体的目标来检验假设。目的1是确定CD 5是否是DC介导的T细胞活化和诱导免疫应答的抑制分子。我们将研究CD 5-/- DC恢复或过度表达CD 5是否抑制其功能并使DC耐受。我们还将研究CD 5对T细胞亚群发育的影响是否是DC CD 5介导的免疫应答作用的机制。目的二是研究DC上表达的CD 5分子是否对效应T细胞具有抑制作用，并调节免疫应答的激发。我们将研究DC上表达的CD 5调节效应T细胞的机制，以及应用具有高水平CD 5表达的DC是否可以使半抗原致敏的动物对半抗原攻击脱敏。目的3研究DC表达的CD 5抑制T细胞活化和DC功能的机制。我们将确定CD 5是否是CD 5介导的T细胞活化抑制的同型配体，或者DC中CD 5介导的信号是否负责DC功能的抑制。该提案的结果将产生新的见解，一个新的作用，CD 5在DC介导的免疫调节，推进我们的理解免疫发病机制的超敏反应性疾病，并提供重要的信息，为发展新的治疗策略。 公共卫生相关性：CD 5是介导T淋巴细胞活化抑制信号的膜蛋白，在炎症性免疫疾病中起重要作用。抗原呈递树突状细胞是T淋巴细胞活化和诱导免疫应答所必需的。目前尚不清楚抗原呈递树突状细胞和T淋巴细胞之间的CD 5-CD 5相互作用是否调节免疫应答。目前的建议将确定抗原呈递树突状细胞的CD 5表达水平是否与其抑制免疫应答中淋巴细胞功能的能力有关。这一结果将阐明CD 5介导的免疫抑制在炎症性疾病中的新机制，并可能被开发为新的治疗策略。

DESCRIPTION (provided by applicant): The immune system is not supposed to react to self-antigens (tolerance) but does recognize and eliminate non-self antigens (immunity). However, over reaction of the immune system to non-self antigens can cause diseases termed hypersensitivity. Contact hypersensitivity (CHS) is a T cell mediated delayed type hypersensitivity response to haptens in the skin. Dendritic cells (DC) are prominent antigen presenting cells for the induction of CHS responses. However, less is known about DC mediated suppressive mechanisms in the immune response. CD5 is a surface molecule which is expressed by T cells and DC. It is well known that CD5 mediates inhibitory signals for T cells and plays important roles in immune tolerance. However, it is unexplored whether CD5 expressed on DC has a role in DC mediated immune regulations. Our preliminary studies have showed that CD5 is expressed by CD11c+ myeloid and lymphoid DC from spleen, lymph node and thymus whereas it is not detectable in plasmacytoid DC. Transfer of hapten labeled CD11c+ DC from CD5 gene knockout (CD5-/-) mice induces a significant higher level of CHS responses than wild type DC. Correspondingly, hapten primed T cells from CD5-/- DC sensitized mice produce higher levels of inflammatory cytokines than those from wild type DC sensitized animals. Further experiments show that CD5-/- DC are more potent than wild type DC to activate CD4+ and CD8+ T cells and induce anti-tumor immunity. These data have for the first time demonstrated that CD5 molecules expressed on DC have an inhibitory effect on DC functions in the activation of T cells and induction of immune responses. The hypothesis of the current application is that the CD5-CD5 interaction between DC and T cells inhibits T cell activation and is an important mechanism for DC induced immune suppression. Three specific aims are proposed to examine the hypothesis. Aim 1 is to determine whether CD5 is an inhibitory molecule for DC mediated activation of T cells and induction of immune responses. We will examine whether restoration or over-expression of CD5 by CD5-/- DC inhibits their functions and renders DC tolerogenic. We will also examine whether an effect of CD5 on the development of T cell subpopulations is a mechanism for DC CD5 mediated effects on immune responses. Aim 2 will determine whether CD5 molecules expressed on DC have an inhibitory effect on effector T cells and regulate the elicitation of immune responses. We will examine mechanism by which CD5 expressed on DC regulates effector T cells and whether application of DC with a high level of CD5 expression can desensitize hapten sensitized animals to hapten challenge. Aim 3 will examine mechanisms by which CD5 expressed on DC inhibits T cell activation and DC function. We will determine whether CD5 is a homotypic ligand for CD5 mediated suppression of T cell activation or CD5 mediated signals in DC are responsible for the suppression of DC functions. The outcome of the proposal will yield new insights into a novel role of CD5 in DC mediated immune regulations, advance our understandings of immune pathogenesis for hypersensitivity diseases, and provide important information for development of new therapeutic strategies. PUBLIC HEALTH RELEVANCE: CD5 is a membrane protein that mediates inhibitory signals for T lymphocyte activation and plays important roles in inflammatory immune diseases. Antigen presenting dendritic cells are required for the activation of T lymphocytes and induction of immune responses. It is unknown whether CD5-CD5 interactions between antigen presenting dendritic cells and T lymphocytes regulate immune responses. The current proposal will determine whether the expression level of CD5 by antigen presenting dendritic cells is related to their ability to inhibit the function of lymphocytes in immune responses. The outcome will elucidate a novel mechanism for CD5 mediated immune suppression in inflammatory diseases and may be exploited to new therapeutic strategies.