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研究生： 葉愛慧
Ai-Hui Yeh
論文名稱： T細胞受體活化反應之模型
Modeling T-cell receptor activation
指導教授： 陳宣毅
Hsuan-Yi Chen
口試委員:
學位類別： 碩士
Master
系所名稱： 理學院 - 生物物理研究所
Graduate Institute of Biophysics
畢業學年度： 99
語文別： 英文
論文頁數： 52
中文關鍵詞： T細胞受體 、T細胞活化 、免疫反應
外文關鍵詞： immune response, CD45, TCR activation, T-cell receptor
相關次數： 點閱：8  下載：0 
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    • 本論文提出一個模型來描述T細胞受體的活化反應。T細胞在辨認帶有病毒蛋白質片段的主要組織相容性複合體(agonist pMHC)時，具有高度的專一性、靈敏度，以及能在短時間內迅速反應之特性。在T細胞受體活化反應過程中也需要蛋白質CD45的協助。我們將單一個T細胞受體活化反應過程簡化為一個對於自由的T細胞受體( free TCR) 和TCR-pMHC複合體而言皆為具有可逆修飾作用的反應模型，並且研究kinetic proofreading mechanism及CD45在T細胞受體活化反應中的效用。研究結果顯示，(1)在缺乏CD45時，kinetic proofreading在合理範圍的pMHC濃度下無法幫助T細胞降低出錯率，其主要原因是由於自由的T細胞受體的去活化速率太過緩慢所導致。(2)當有CD45存在時，T細胞受體可加速進行去活化反應。因此當活化反應所經過的步驟較多時，在模擬中self pMHC幾乎很難使T細胞受體達到完全活化的階段。由此可知CD45對於T細胞受體活化反應的專一性而言是不可缺少的。另外，增加活化反應步驟的數目也有助於提高T細胞受體的專一性。(3) 如果在活化反應過程中，未與pMHC形成複合體的T細胞受體不擴散到T細胞與抗原呈現細胞間最近接觸區域之外，則此T細胞受體就有機會能再和pMHC分子產生鍵結並繼續進行其活化反應。藉由這種方式，self pMHC便能夠協助T細胞受體進行活化反應，並有助於提高T細胞受體活化反應之靈敏度與加快活化反應速率。

    We propose a model that describes the initial process of T-cell receptor (TCR) activa-
    tion. An e cient T cell can recognize agonist pMHC with high speci city, sensitivity,
    and speed. The assistance of CD45 is also required for TCR activation. We consider
    the simulation for single TCR activation that is simpli ed as a reversible modi cation
    levels for both free TCR and TCR-pMHC complex. We discuss the e cacy of kinetic
    proofreading mechanism and CD45 in TCR activation. Our study reveals that (i) In
    the absence of CD45, kinetic proofreading fails at reasonable pMHC concentrations
    due to the slowness of deactivation processes for free TCR. (ii) In the presence of
    CD45, TCR can be deactivated quickly. Even when there are few activation steps,
    it is di cult that self pMHC fully activate the TCR during the simulation. It means
    that CD45 is very essential for the speci city of TCR activation and increasing the
    number of activation steps is helpful for TCR speci city. (iii) If a free TCR does not
    di use out of the close contact region between the T cell and the antigen-presenting
    cell, it can bind with a pMHC and continues to move to higher activation level. That
    indicates the possibility for self pMHC to help TCR activation, and it may eventually
    explain the sensitivity and speedy of TCR activation.

    1 Introduction 1 1.1 Biochemistry of TCR activation . . . . . . . . . . . . . . . . . . . . . 2 2 Background and Simulation Method 7 2.1 Kinetic proofreading mechanism . . . . . . . . . . . . . . . . . . . . . 7 2.2 Kinetic proofreading models of T-cell receptor activation . . . . . . . 11 3 Simulation the activation of a single TCR 15 3.1 Metropolis algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.2 Monte Carlo simulation for a single T cell receptor . . . . . . . . . . 16 3.3 The energy landscape and the rate equations in our model for single TCR activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 3.4 Kinetic proofreading and CD45 in our model . . . . . . . . . . . . . . 22 3.5 Parameters in the model . . . . . . . . . . . . . . . . . . . . . . . . . 23 4 Result and Discussion 28 4.1 Numerical Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.2 Possible mechanisms for the sensitivity and speedy of TCR activation 35 5 Summary and Future Work 39 A Lattice Simulation 42 A.1 Simulation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

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