The Role of CD5 In Dendritic Cell Mediated Immune Suppression

说明(申请人提供)：免疫系统不应该对自身抗原(耐受性)做出反应，但可以识别和消除非自身抗原(免疫)。然而，免疫系统对非自身抗原的过度反应可能会导致称为超敏反应的疾病。接触性超敏反应(CHS)是一种T细胞介导的皮肤对半抗原的迟发性超敏反应。树突状细胞(DC)是诱导CHS反应的重要抗原提呈细胞。然而，对DC介导的免疫反应抑制机制知之甚少。CD5是一种由T细胞和DC表达的表面分子。众所周知，CD5介导T细胞的抑制信号，在免疫耐受中发挥重要作用。然而，树突状细胞表面表达的CD5是否在树突状细胞介导的免疫调节中起作用尚不清楚。我们的初步研究表明，CD11c+的髓样和淋巴样DC在脾、淋巴结和胸腺表达CD5，而在浆细胞样树突状细胞中不表达CD5。CD5基因敲除(CD5-/-)小鼠半抗原标记的CD11c+DC诱导的CHS应答水平显著高于野生型DC。相应地，CD5-/-DC致敏小鼠半抗原诱导的T细胞产生比野生型DC致敏动物更高水平的炎性细胞因子。进一步的实验表明，CD5-/-DC比野生型DC更能激活CD4+和CD8+T细胞，诱导抗肿瘤免疫。这些数据首次证明，DC表面表达的CD5分子在激活T细胞和诱导免疫反应方面对DC功能具有抑制作用。目前的应用假设是，DC和T细胞之间的CD5-CD5相互作用抑制了T细胞的激活，是DC诱导免疫抑制的重要机制。为了检验这一假说，本文提出了三个具体目标。目的1确定CD5是否是DC介导的T细胞活化和免疫应答的抑制分子。我们将研究CD5-/-DC恢复或过度表达CD5是否抑制其功能，并使DC具有耐受性。我们还将研究CD5对T细胞亚群发育的影响是否是DC CD5介导的免疫反应的机制。目的2研究树突状细胞表面表达的CD5分子是否对效应性T细胞有抑制作用，并调节免疫应答的激发。我们将研究DC上表达的CD5调节效应T细胞的机制，以及应用高表达CD5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将研究CD5在DC上表达抑制T细胞激活和DC功能的机制。我们将确定CD5是否是CD5介导的抑制T细胞活化的同型配体，还是CD5介导的信号在DC中对DC功能的抑制负责。该研究的结果将对CD5在DC介导的免疫调节中的新作用提供新的见解，促进我们对过敏性疾病免疫发病机制的理解，并为开发新的治疗策略提供重要信息。 与公共卫生相关：CD5是一种膜蛋白，介导T淋巴细胞激活的抑制信号，在炎症性免疫疾病中发挥重要作用。抗原提呈树突状细胞是激活T淋巴细胞和诱导免疫反应所必需的。目前尚不清楚抗原提呈树突状细胞和T淋巴细胞之间的CD5-CD5相互作用是否调节免疫反应。目前的提议将确定抗原提呈树突状细胞CD5的表达水平是否与其在免疫反应中抑制淋巴细胞功能的能力有关。这一结果将阐明CD5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.