CD43 - a molecular switch for efferocytosis and HIV-1 infection

免疫系统的进化主要是为了保护我们免受微生物的感染，因此需要对感染做出快速而有力的反应。然而，过度强烈或持续的免疫应答可能对宿主造成损害，导致过度炎症和最终持续性免疫疾病如自身免疫。因此，需要仔细调节免疫系统以预防此类疾病。实现这一点的一种方法是使用蛋白质，防止免疫细胞之间发生不适当的强烈相互作用。一种这样的蛋白质是CD 43，在免疫细胞如T淋巴细胞上发现，它具有延伸的杆状结构，并远远超出细胞膜的“糖衣”，即所谓的糖萼。因此，CD 43可以简单地通过其大小来抑制细胞之间的相互作用。然而，CD 43的第二种抑制活性是它的强负电荷，这将排斥其他带类似电荷的免疫细胞。鉴于CD 43是一种有效的调节分子，细胞如何克服这一障碍，在需要时进行强烈的相互作用？我们最近发现，在某些信号，包括细胞死亡和感染的人类免疫缺陷病毒1型（HIV-1），CD 43是迅速失去从细胞表面。CD 43的丢失导致这些细胞被另一种称为巨噬细胞的免疫细胞识别为受损，巨噬细胞捕获，吞噬和破坏这些受损细胞。这个过程是对局部组织环境的必要清理，并且需要防止可能释放其内容物的受损和垂死细胞的建立，从而引发不必要的炎症。然而，一些致病微生物，如HIV-1，已经进化到利用死亡或受感染细胞与巨噬细胞之间的接触，跳进巨噬细胞并感染它。这种类型的病毒传播允许更快的病毒传播和繁殖，增加疾病和持久性。我们已经发现，HIV-1感染辅助性T淋巴细胞会引发细胞表面CD 43的丢失，部分原因是病毒诱导细胞死亡。如上所述，CD 43的丢失吸引巨噬细胞吞噬这些感染的T细胞，然后感染又传递给巨噬细胞。这种类型的细胞间传播非常有效，并允许巨噬细胞感染通常不会感染它们的HIV-1菌株。另一个考虑因素是T辅助细胞上的CD 43作为HIV-1感染的屏障，因此我们也将研究CD 43的丢失如何使这些细胞更容易受到HIV-1感染，以及我们如何预防这种情况。我们已经确定了一种名为ADAM 10的分子，它导致死亡和感染的T淋巴细胞表面CD 43的丢失。ADAM 10是一种细胞表面酶，当被感染或细胞死亡激活时，它会在其基部切断CD 43，将其从细胞中释放出来。目前，我们还不知道细胞死亡和HIV-1感染是如何触发ADAM 10激活的，这是我们在本申请中要解决的主要问题之一。一旦我们了解了细胞死亡和感染是如何开启ADAM 10的，我们就可以测试药物来抑制或增强这一过程。如果成功的话，这些药物可能会通过防止受感染的T细胞的CD 43丢失来减缓HIV-1对T细胞和巨噬细胞的感染，或者加速可能参与炎症性疾病的死亡和死亡细胞的清除，如心血管疾病（例如，心脏病）。动脉粥样硬化）和自身免疫（例如，系统性红斑狼疮）疾病。

The immune system has evolved primarily to protect us from infection by microbes, and therefore needs to respond rapidly and robustly to infection. However excessively strong or sustained immune responses can be damaging to the host, resulting in disease from excess inflammation and ultimately persistent immune disorders such as autoimmunity. The immune system therefore needs to be carefully regulated to prevent such disease. A way that this may be achieved is by the use of proteins that prevent strong interactions from occurring inappropriately between immune cells. One such protein is CD43, found on immune cells such as T lymphocytes, that has an extended rod-like structure and projects well beyond the 'sugar-coat' of the cell membrane, the so-called glycocalyx. CD43 may thus inhibit interactions between cells simply by its size. However a second inhibitory activity of CD43 is its strong negative charge that will repel other similarly charged immune cells. Given that CD43 is a potent regulatory molecule, how might cells overcome this barrier to interact strongly when required? We have recently found that upon certain signals, including cell death and infection by the human immunodeficiency virus type-1 (HIV-1), CD43 is rapidly lost from the cell surface. The loss of CD43 results in these cells being recognised as damaged by another immune type of cell called a macrophage, that captures, engulfs and destroys these damaged cells. This process is an essential clean up of the local tissue environment and is required to prevent the build of of damaged and dying cells that may release their contents, triggering unwanted inflammation. However, some disease causing microbes, such as HIV-1, have evolved to use the contact between dying or infected cells and macrophages to jump into the macrophage and infect it. This type of viral spread allows faster viral spread and multiplication, increasing disease and persistence. We have found that infection of T helper lymphocytes by HIV-1 triggers loss of CD43 from the cell surface, in part by the virus inducing cell death. As described above, loss of CD43 attracts macrophages to engulf these infected T cells, and the infection is then passed in turn to the macrophages. This type of cell-to-cell spread is very efficient and allows macrophage infection by HIV-1 strains that would not usually infect them. An additional consideration is that CD43 on T helper cells acts as a barrier to HIV-1 infection, and so we will also investigate how the loss of CD43 makes these cells more susceptible to HIV-1 infection and how we might prevent this.We have identified a molecule called ADAM10 that causes the loss of CD43 on the surface of dying and infected T lymphocytes. ADAM10 is a cell-surface enzyme that when activated by infection or cell death cuts off CD43 at its base, releasing it from the cell. At present we do not know how cell death and HIV-1 infection trigger ADAM10 activation, and this is one of the main questions we will address in this application. Once we understand how ADAM10 is switched on by cell death and infection we can test drugs to inhibit or enhance this process. If successful, these drugs might then be used to either slow down HIV-1 infection of T cells and macrophages by preventing CD43 loss from infected T cells, or speed up the clearance of dying and dead cells that may be involved in inflammatory conditions such as cardiovascular (eg. atherosclerosis) and autoimmune (eg. systemic lupus erythematosus) diseases.