Role of MHC Class I Molecules in Shaping Developmental and Functional Fate of CD4+ T Lymphocytes

• Main Authors: Fen-Ling Chen, 陳芬苓
• Other Authors: John T. Kung
• Format: Others
• Language: zh-TW
• Published: 2000
• Online Access: http://ndltd.ncl.edu.tw/handle/69302021532462632419

博士 === 國立臺灣大學 === 免疫學研究所 === 88 === Most CD4+ T cells of MHC class I (H-2Ld)-restricted 2C TCR transgenic mice expressed markers characteristic of memory T cells and proliferated poorly in response to stimulation by anti-CD3 and by PMA plus ionomycin. The deficient proliferative response by 2C CD4+ T cells was not due to positional effect of transgene insertion, because CD8+ T cells from the same mice functioned well. However, 2C+ CD4+ T cells did produce IL-2, IL-4 and expressed IL-2Ra, b and g chains upon anti-CD3 stimulation, ruling out a generalized dysfunction in TCR signal transduction pathway. Similar deficiency of CD4+ T cell proliferative response was observed in male H-Y TCR transgenic mice expressing TCR specific for male antigen in the context of H-2Db. These observations raised the possibility that MHC class I molecules may play an important role in shaping CD4+ T cell development and function. To address this possibility, CD4+ T cells from 2C and HY transgenic mice on MHC-I-deficient background were studied. Surface markers and cellular function in both these two mouse strains reversed to levels comparable to control transgene-negative littermates. Breeding 2C TCR transgenic mice onto MHC-II-deficient background resulted in nearly complete disappearance of CD4+ T cells. Those CD4+ T cells generated on the MHC-II deficient background, although with very few numbers, all expressed transgenic TCR. When 2C TCR transgenic mice bred onto RAG-1-knockout background, similar disappearance of CD4+ T cells was observed. These results suggested that the CD4+ T cells on 2C TCR transgenic mice rearranged their endogenous TCR genes and were selected by MHC-II molecules. Upon allogenic dendritic cell stimulation, the IL-2 production by 2C CD4+ T cells could be inhibited by anti-CD4 or anti-MHC-II mAb. These data indicated that the development of 2C CD4+ T cells required MHC-II engagement and these CD4+ T cells were MHC-II restricted. The unique CD4+ T cell subset observed on 2C MHC-I-restricted TCR transgenic mice expressed diverse TCR b chain usage and can produce significant level of IL-4 during primary plate-bound anti-CD3 + anti-CD28 stimulation. MHC-I can therefore influence CD4+ T cell development and function. We propose that the interaction of transgenic TCR and MHC class I molecules during CD4+8+ developmental stage can influence CD4+ T cell function and the CD4 : MHC II interaction can provide positive selection signals that drive their development into CD4+ T cells. Such CD4+ T cells may play a role in the modulation of immune response by produced cytokine profiles. Although the in vivo function of such CD4+ T cells is not fully understood, these results raise interesting possibilities and complexities in the regulation of T cell development and immune response.