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反应可能对宿主造成损害，导致过度炎症导致疾病，最终导致持续的免疫紊乱，如自身免疫。因此，需要仔细调节免疫系统以预防此类疾病。实现这一目标的一种方法是使用蛋白质来防止免疫细胞之间发生不适当的强烈相互作用。其中一种蛋白质是CD43，存在于T淋巴细胞等免疫细胞中，它具有延伸的棒状结构，远远超出了细胞膜的“糖衣”，即所谓的糖萼。因此，CD43可能仅仅通过其大小就能抑制细胞间的相互作用。然而，CD43的第二种抑制活性是其强烈的负电荷，它会排斥其他带有类似电荷的免疫细胞。考虑到CD43是一种有效的调节分子，细胞如何在需要时克服这一屏障进行强烈的相互作用呢？我们最近发现，在某些信号，包括细胞死亡和感染人类免疫缺陷病毒1型（HIV-1）， CD43从细胞表面迅速丢失。CD43的缺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细胞，巨噬细胞捕获、吞噬并摧毁这些受损细胞。这个过程是对局部组织环境的必要清理，并且需要防止受损和死亡细胞的形成，这些细胞可能会释放出它们的内容物，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感染细胞与巨噬细胞之间的接触，跳入巨噬细胞并感染它。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。我们发现，HIV-1感染辅助性T淋巴细胞会触发细胞表面CD43的丢失，部分原因是病毒诱导细胞死亡。如上所述，CD43的缺失吸引巨噬细胞吞噬这些被感染的T细胞，然后感染依次传递给巨噬细胞。这种细胞间传播非常有效，并且允许巨噬细胞感染通常不会感染它们的HIV-1毒株。另一个考虑因素是T辅助细胞上的CD43作为HIV-1感染的屏障，因此我们也将研究CD43的缺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叫做ADAM10的分子，它会导致死亡和感染T淋巴细胞表面CD43的丢失。ADAM10是一种细胞表面酶，当被感染或细胞死亡激活时，它会切断CD43的基部，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ADAM10激活的，这是我们将在本应用中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ADAM10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，这些药物可以通过防止CD43从被感染的T细胞中丢失来减缓T细胞和巨噬细胞对HIV-1的感染，或者加速对可能涉及心血管疾病（如心血管疾病）等炎症的死亡细胞的清除。动脉粥样硬化)和自身免疫(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.