2001 Fiscal Year Final Research Report Summary
Development of a new approach for immunosuppression on the basis of expression regulation of CTLA-4
| Project/Area Number |
12557021
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 展開研究 |
|---|
| Research Field |
Experimental pathology
|
|---|
| Research Institution | CHIBA UNIVERSITY |
|---|
Principal Investigator |
SAITO Takashi Chiba University, Graduate School Of Medicine, Professor, 大学院・医学研究院, 教授 (50205655)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YAMASAKI Sho Chiba University, Graduate School of Medicine, Assistant, 大学院・医学研究院, 助手 (40312946)
|
|---|
| Project Period (FY) |
2000 – 2001
|
| Keywords | CTLA-4 / T cell activation / inhibitory signal / Rap-1 / immuno synapse / tyrosine signal / SPA-1 / LFA-1 |
|---|
| Research Abstract |
The cell surface expression and mechanism of negative signal transduction of CTLA-4 was analyzed. In addition to our previous findings that CTLA-4 is endocytosed by the interaction with AP-2 through the tyrosine signal within the cytoplasmic tail of CTLA-4, we observed that CTLA-4 is accumulated mainly in lysosome and degradated in the absence of TCR stimulation. Upon TCR stimulation, CTLA-4-containing lysosome is somehow fused with the plasma membrane that induces high expression of cell surface CTLA-4 as well as secretion of several lysosomal enzymes. We have screened fifty thousand of various compounds for their inhibitory function of the interaction between CTLA-4 and AP-2 using yeast two hybrid system. However, unfortunately, we could not obtain any specific inhibitory molecule/compound. Other approaches will be required such as screening of inhibitors of the responsible phosphatase for CTLA-4 dephosphorylation which may be responsible for maintaining the Cell surface expression of CTLA-4. Regarding to the inhibitory function of CTLA-4, we identified the transmembrane and/or membrane-proximal region to be responsible for CTLA-4-mediated suppression. This result excludes the possibility that SHP-2 or PI3-K is not responsible for the suppression. During the search of the responsible mechanism of CTLA-4-mediated inhibition, we found that CTLA-4 crosslinking induces activation of Rap-1. Expression of Rap-1GAP into T cells results in the failure of CTLA-4-induced suppression. Furthermore, high expression of the cell surface CTLA-4 induced early termination of immune synapse formation and Rap-1GAP-expressed T cells exhibits prolonged synapse formation. Therefore, CTLA-4 induces Rap-1 activation and prevents the maintenance of immune synapse formation. These finding may provide a new approach for immune disorders by modulating CTLA-4-mediating inhibitory signals.
|
