CONCLUSION

In this study, the molecular mechanisms for the inhibitory function of TIM3 in Th1-mediated cytokine production was investigated and reduced activities of AP-1 and NFAT through defect in c-Jun expression and NFAT dephosphorylation, were found in TIM3 expressing cells. Further, the C-terminal region was shown to be important in suppression of IL-2 and IFN-γ expression as well as in inhibition of activities of AP-1 and NFAT. In the evaluation of the effect of Tim3-hIg expression on tumor progression, I found that Tim3-hIg expression in tumor cells decreased tumor growth and that Tim3-hIg expression increased efficacy of the whole cell tumor vaccine. Taken together, these results expand the knowledge about function of TIM3.

.

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TIM3의 세포 내 부위 중 E²⁶¹와 I²⁶⁷사이에 존재하는 7개의 아미노산이

필요하다는 결과를 관찰하였다. E²⁶¹부터 P³⁰¹까지의 아미노산이 AP-1의 활성

억제에 관여하며 E²⁷⁸부터 P³⁰¹까지의 아미노산이 NFAT의 활성 억제에

관여한다는 결과를 관찰하였다.

다음으로 TIM3 경로 억제 분자 Tim3-hIg 가 종양 증식에 미치는 영향을 분석하였다. 마우스에서 3LL 세포의 증식은 Tm3-hIg 발현으로 감소하였으며, 조절 T 세포의 빈도도 감소하는 경향이 나타났다. 또한 Tim3-hIg 의 발현은 예방성 종양 백신 (prophylactic tumor vaccine)과 치료성 종양 백신 (therapeutic tumor vaccine)의 효능을 증대시켰다. 그러나 Tim3-hIg 를 화학 치료제인 5-Fu 와 함께 투여하였을 때 종양 억제 효과의 증대는 유도되지 않았다. 이러한 결과들은 TIM3 가 AP-1 과 NFAT 의 활성을 조절하는 기작에 관여하여 인터루킨 2 의 생산과 같은 T 세포의 활성화를 억제하고, TIM3 경로 억제 분자가 종양 백신의 효능과 종양에 대한 면역 반응을 증대시킨다는 것을 제시한다.

핵심어: TIM3, 보조 T 세포 1 형, 인터루킨 2, 인터페론 γ, AP-1, c-Jun, NFAT, Tim3-hIg, 조절 T 세포, 종양 백신