| 摘要: | 介白素15號(interleukin-15, IL-15)為一個14-15 kD之細胞激素，於造血細胞、表皮細胞等多型態細胞中均可偵測其表現。IL-15受器(receptor, R)由?恁B?牷B?蚺T個蛋白質所組成，其中，?捙鴐衰L-15R所特有，對IL-15具高度親和性；?狺??袓鴢h與IL-2R共用，對IL-15具中度親和性。IL-15基因刪除 (IL-15 knock-out, IL-15-/-)及 IL-15R??-/-小鼠之自然殺手細胞T 細胞、記憶型CD8+ T細胞及CD8????+ 小腸上皮內淋巴細胞(intestine intraepithelial lymphocytes, iIEL)均減少90%以上。口服免疫耐受性為自我耐受性中的一種形式，若小鼠以口服方式接受抗原後，再以相同抗原伴隨輔助劑給予刺激，則其免疫系統會降低對該抗原之反應時稱之。隨著餵食抗原劑量不同，口服免疫耐受性可產生不同機制：餵食低劑量抗原時，可誘使調節性T細胞(regulatory T cell, Treg cell)產生，並釋放出轉型生長因子(transforming growth factor, TGF)-?牷BIL-4及IL-10；餵食高劑量抗原時，則會造成抗原專一性T細胞系刪除(clonal deletion)或失去活化能力(anergy)。Treg cell除了可調節外來抗原所產生之耐受反應外，亦可抑制自我反應之T細胞。我們實驗室曾於Il15-/-及Il15ra-/-小鼠中發現自體抗體之表現。說明於Il15-/-及Il15ra-/-小鼠中，其Treg cell可能失去抑制細胞活化之功能。此外，CD103+樹突細胞(dendritic cell, DC)可影響Treg cell抑制抗原專一性細胞活化之反應，我們亦發現Il15-/-及Il15ra-/-小鼠具有較少比例之CD103+ DC。因此，我假設IL-15可藉由CD103+ DC及Treg cell影響口服免疫耐受性之產生。此篇論文中，我們使用帶有可辨識鷄卵白蛋白(ovalbumin, OVA) 胜肽鏈(peptide)323-339片段之轉基因TCR的WT, Il15-/-及Il15ra-/-小鼠，以探討IL-15系統與誘發口服免疫耐受性之關聯。結果顯示，三基因型小鼠餵食OVA後，其腸繫膜淋巴結(mesenteric lymph node cell, MLN)細胞可降低對OVA再刺激之反應性；而其Treg cells (包含CD25+Foxp3+及CD25+CD103+ CD4+ T 細胞)及CD103+ DC之細胞比例卻不因餵食OVA而有所改變。因此說明，OT-II轉基因小鼠於誘發口服免疫耐受性產生時，並不受IL-15影響。
Interleukin-15 (IL-15) is a 14-15 kD protein, expressed by hematopoietic cells as well as by most other types of cells. IL-15 receptor (IL-15R) consists of ??, ??, and the common ?? (?莕) chain. The ?? and ?莕 chains form intermediate affinity receptor for IL-15 and IL-2, while the ?? chain is exclusive for binding IL-15 with high affinity even in the absence of the ???莕 subunits. Il-15 knock-out (Il15-/-) and Il15ra-/- mice show severe deficiency in natural killer cells (NK), NKT cell, memory CD8+ T cells, and CD8????+ intestine intraepithelial lymphocytes (iIEL). Oral tolerance is a form of self tolerance in response to non-harmful antigens came through the intestine. It refers to the phenomenon that feeding a rodent with soluble protein rendered the animal hyporesponsive to parenteral immunization with the same protein plus adjuvant. Different mechanisms underlie oral tolerance depending on the dose of fed antigen. Low dose antigen induces antigen-specific regulatory T cells (Treg cells), which produce inhibitory cytokines such as transforming growth factor-?? (TGF-??), IL-4, and IL-10. High dose antigen may result in anergy/deletion of antigen-specific T cells. In addition to tolerance to non-harmful foreign antigens, Treg cells inhibit activation of autoreactive T cells in the periphery. Our lab found that aged female Il15-/- and Il15ra-/- mice produced autoantibodies, implicating dysfunction of Treg cells in these mice. We also found that Il15-/- and Il15ra-/-mice harbor less frequency of CD103+ dendritic cells (DC) compared to wild-type (WT) mice. CD103+ DC is required for the suppressive function of Treg cells in oral tolerance. Therefore, I hypothesize that IL-15 positively modulate oral tolerance induction through CD103+ DC and Treg cells. In this thesis, I determined the role of the IL-15 system in oral tolerance induction by comparative analysis of WT, Il15-/- and Il15ra-/- mice expressing the transgenic T cell receptor that recognizes an ovalbumin (OVA) peptide 323-329 presented by I-Ab. I found that mesenteric lymph node cells in all three types of mice fed with OVA showed reduced response to OVA re-stimulation in vitro. Moreover, the frequencies of Treg cells, CD25+Foxp3+ and CD25+CD103+ CD4+ T cells, and the frequence of CD103+ DC were similar among WT and knock-out mice fed with OVA or PBS. These results suggest that IL-15 system is not required for oral tolerance induction in OT-II mice. |
