本間 利夫 東京大学, 医科学研究所, 教務職員 (10282526)
HOSONO Osamu The University of Tokyo, Institute of Medical Science, Assistant Professor, 医科学研究所, 助手 (50190210)
KAWASAKI Hiroshi The University of Tokyo, Institute of Medical Science, Assistant Professor, 医科学研究所, 助手 (80280957)
野島 美久 群馬大学, 医学部, 助教授 (90201699)
|Budget Amount *help
¥33,700,000 (Direct Cost : ¥33,700,000)
Fiscal Year 1998 : ¥8,700,000 (Direct Cost : ¥8,700,000)
Fiscal Year 1997 : ¥25,000,000 (Direct Cost : ¥25,000,000)
In the present study, we attempted to define the molecular basis of role of CD26 and CD27 molecules in T cell immune regulation and their clinical significances. To characterize the role of CD27-mediated signaling in B cell responses, we have compared the effects of CD27 and CD4O ligation on B cell proliferation, IgG production, and cell phenotype. We demonstrate that, in contrast to CD40, CD27 signaling plays a minor role in B proliferation and that its major function, which is delayed during the process of B cell differentiation, is to contribute to the formation of Ig-producing cells.
CD26, a 110 kDa cell surface glycoprotein, exhibits dipeptidyl peptidase IV (DPPIV ; EC22.214.171.124) enzyme activity and plays an important role in T cell costimulation. The function of CD26/dipeptidyl peptidase IV in transendothelial migration was examined using beta-chemokines as chemoattractants. When soluble recombinant CD26 (CD26/DPPIV^+) was added to the transendothelial chemotaxis system, chemotactic
migration of T cells toward RANTES was significantly enhanced. Addition of sCD26 to 50 ng/ml of RANTES enhanced the migratory response by a factor of two compared to RANTES alone, whereas mutant soluble CD26, lacking the DPPIV enzyme activity, had no enhancing effect on RANTES-induced T cell migration. In the process of analyzing the mechanisms of the enhancement of T cell migration by sCD26, we showed that RANTES was cleaved by sCD26 under physiologic conditions at the precise site characteristic of its enzyme specificity. However, synthesized RANTES which lacks two N-terminal amino acids showed a chemotactic activity equivalent to full length RANTES on T cells. Furthermore, addition of sCD26 showed enhancement of T cell migration induced by both forms of RANTES.In contrast to T cells, the truncated RANTES is inactive in chemotaxis of purified monocytes, and supplement of sCD26 but not mCD26 reduced the migratory response of monocytes to RANTES.These results suggest that CD26/DPPIV differentially regulate the chemotactic response of T cells and monocytes to RANTES and furthermore, the finding can partly explain the observation that CD26 highly positive cells have most migratory capacity in vitro and were the dominant phenotype at the chronic inflammatory sites in vivo.
RANTES同様にSDF-1αとsCD26を反応させ、アミノ酸配列を検討したところ、N末端の2番目のプロリンのC末端側で切断された。この様にRANTES,SDF-1αともにCD26/DPPIVの基質であることが明らかになった。SDF-1αとCD26/DPPIVの相互作用がT-tropicウィルス感染における影響を検討した。SDF-1αによるHIVの細胞侵入の阻害はsCD26を添加することによりその阻害活性は失われた。さらに、リンパ球遊走能の亢進作用も消失した。この様にCD26/DPPIVはin vivoにおいてHIV感染や炎症反応を制御する分子として重要であることが示唆された。 Less