PSGL-1引發活化T細胞死亡之分子機制探討

Molecular Mechanisms of P-selectin Glycoprotein Ligand-1-Mediated Cell Death in Activated T Cells

陳淑靜(Shu-Ching Chen)

指導教授 ： 林榮華

國立臺灣大學/醫學院/免疫學研究所/博士(2004年)

https://doi.org/10.6342/NTU.2004.02434

摘要

摘 要

我們身體的免疫系統發展出上許多精緻細微的策略用以調控免疫反應。一般來說，當T細胞 (Naïve T cells) 接觸到其特定抗原之後，這些T細胞會增生，進一步分化成為具有特定功能的細胞 (Effector T cells)。而當外來致病原被消滅殆盡後，大部分這些活化的T細胞也會被清除掉，以維持生體內T細胞族群的恆定。因此，在免疫反應的不同階段中，T細胞的生死命運一直都被嚴密調控著。

許多年來，研究發現，細胞死亡受體 (例如Fas與TNF receptors家族) 以及由它們所引發的死亡訊息之傳遞路徑，對於調節活化性T細胞有其相當之重要性。 而在最近數年中，有越來越多的證據顯示，有其他不同於目前已知的死亡受體之分子，也可以引發活化性T細胞死亡。同時，抑制傳统已知的死亡訊息路徑中之Caspases的活性，並不能防止T細胞發生死亡。這就明白地指出，活化性T細胞的死亡訊息是被非常複雜的方式所調控。

我們為了要進一步明瞭活化性T細胞的死亡機制，我們研究室產製了許多批可對抗小鼠活化性T細胞的單株抗體，並篩選出具有誘發
小鼠活化性T細胞死亡的細胞株。其中，效果最顯著的一株名為TAB4。目前知道TAB4可以辨識P-selectin glycoprotein ligand-1, PSGL-1 (亦稱CD162)。

目前已知在發炎反應中，藉由PSGL-1與selectins之間的交互作用，可以引發白血球的遷移。在本研究中，我們利用抗PSGL-1的單株抗體，TAB4，首次於全世界證實交合的PSGL-1 (cross-linking of PSGL-1) 可以引發活化性T細胞之死亡。相較於傳统的細胞死亡訊息，PSGL-1所引起的細胞死亡是不經由Caspases的作用，反而是經由凋亡誘發因子 (Apoptosis-inducing factor, AIF) 自粒腺體轉位到細胞核中，以及細胞色素c (cytochrome c) 自粒腺體釋放到細胞質所造成。從細胞的細微結構來看，在以TAB4交合細胞上的PSGL-1誘發活化性T細胞死亡過程中，可觀察到細胞染色質聚集在細胞核的周邊和細胞凋亡體的發生。在我們現今的研究顯示，固定的P-selectin或Ｅ-selectin也具有誘發活化性T細胞死亡的效果。總括而言 我們的研究顯示了PSGL-1一個全新的角色，亦即PSGL-1可以控制活化性T細胞死亡。如此一來，使我們對免疫調控有更進一步的了解。

我們進行本研究的主要意圖，是要清楚地剖析決定活化性T細胞
死亡的分子機制。並且，藉由這個研究，可更明確說明這些分子機制的整合，有助於了解T細胞在體內的恆定過程。

關鍵字

T細胞死亡

並列摘要

Abstract

The immune system evolves several sophisticated strategies to regulate immune responses. In general, contact with their specific antigen causes naïve T cells to proliferate and differentiate into effector cells. After the pathogen is destroyed, most effector T cells are eliminated, thereby preserving the size of T cell repertoire. During each stage of this process, the fate of life or death of T cells is strictly regulated.

For many years, the importance of death receptors such as Fas and other TNF receptor family members as well as depiction of death signaling pathway have been emphasized in regulation of activated T cells. In recent years, however, increasing evidence has shown that molecules other than death receptors can also trigger T-cell death. Inhibition of classical caspases can not always prevent T cell death. These observations indicate that death signaling in activated T cells is regulated in a very complicated way.

In order to address the death mechanisms of activated T cells, panels of hamster monoclonal antibodies against mouse activated T cells were generated in our laboratory. Those antibodies with death-triggering function on mouse activated T cells were screened. The most significant one, named TAB4, was found to recognize P-selectin glycoprotein ligand-1 (PSGL-1) or CD162.

PSGL-1 is well known for mediating leukocyte trafficking by interaction with selectins during inflammatory responses. Using the anti-PSGL-1 monoclonal antibody, TAB4, here we demonstrate for the first time that cross-linking of PSGL-1 can trigger a death signal in activated T cells. In contrast to classical cell death, PSGL-1-mediated T cell death is caspase-independent. It involves translocation of apoptosis-inducing factor from mitochondria to nucleus as well as mitochondrial cytochrome c release. Ultrastructurally, both peripheral condensation of chromatin and apoptotic body were observed in PSGL-1-mediated T-cell death. In present study, immobilized P- or E- selectin is also demonstrate to have death-triggering effect on activated T cells. Collectively, this study demonstrates a novel role of PSGL-1 in controlling activated T-cell death and thus advances our understanding of immune regulation.

Our intent in this study is to clarify the molecular mechanisms that determine death of activated T cells and to indicate how these can be integrated into a more complete description of the T cell homeostasis.

並列關鍵字

P-selectin Glycoprotein Ligand-1, T cell death

參考文獻

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