| Backgroud: The antigen specific celluar immune response mediated by CD8+ cytotoxic T lymphocytes (CD8+ CTL) play a crucial role in the antitumor responses of the immune system. However, the proliferation and the priming of the tumoricidal activity need the help of the CD4+ T lymphocytes and the presentation of the tumor antigen by mature dendritic cells(DCs).The help of the CD4+ T lymphocytes mediated by CD154/CD40 signal pathway leads to the induction of fully mature DCs having the ability to present antigens and stimulate CD8+ CTLs. CD154(CD40L,TRAP, gp39) is a member of the tumor necrosis factor gene family. It is a 33kDa type II membrane glycoprotein consists of 261 amino acids. It is transiently expressed primarily by activated CD4+ T lymphocytes, a proportion of activated CD8+ T lymphocytes and Y 5 T lymphocytes. And it is an important costimulatory molecule participating in both humoral and cellular immune responses.CD40, the receptor of CD 154 protein, belonging to the tumor necrosis factor receptor superfamily, is a type I transmembrane glycoprotein of 48kDa, consists of 217 amino acids. It is physiologically expressed by B lymphocytes, monocytes, endothelial cells, DCs, follicular dendritic cells (FDCs), macrophages, epithelial cells and hematopoietic stem/progenitor cells, and is also expressed on a variety of carcinomas.CD40/CD154 interactions not only drive B lymphocytes activation, differentiation, proliferation, antibody secretion and immunoglobulin class swithching, but the two-way signals transmitted via CD40/ CD40L ineractions between CD4+Tlymphocytes, DCs, CD8+ T lymphocytes are the pivotal pathways controlling the activation, proliferation and differentiation of T lymphocytes and DCs, the initiation and maintenance of the specific cellular immune response, the generation of CD8+ T lymphocyte memory. The effects of CD40/CD154 interactions on the development,matuiation of DCs as well as on their antigen presention and immune stimulating functions are as follows . (1) The proliferation,development,maturation of DCs are promoted by CD154/ CD40 signal. And the costimulatory molecules on immature DCs are upregulated by CD 1547 CD40 signal as well.(2) CD40 triggering on DCs leads to their migration from the periphery to draining lymph nodes and the survival of DCs in lymph nodes,the number of DCs which are capable of antigen presention are increased as a result.Furthermore, the period for which DCs can productively present antigens are dramatically prolonged.(S) The secretion of IL-12 by DCs are promoted by CD40 engagement by CD 154, which contribute to the induction of Thl response and cytotoxic T lymphocyte response.(4) The secretion of proinflammatory cytokines such as IL-1 , IL-6, IFN- Y , TNF- a are enhanced which lead to further activation, maturation and immune stimulation activity of DCs. (5) OXCD40L, 4-lBBL and CD27L(CD70), the important costimulatory molecules implicated in T lymphocytes proliferation, activation are upregulated on DCs. The interaction between OXCD40L expressed on mature DCs and OXCD40 on the cell surface of activated CD8+ T lymphocytes advance the activation and differentiation of T lymphocytes and DCs. B7/CD28 costimulatory pathway is co-ordinated with the 4-1BBL/4-1BB signal transduction ,The activation induced cell death of mature T lymphocytes is suppressed consequently. 4-lBBL and CD27L(CD70) not only provide important survival signal to proliferating CD8+ T lymphocytes, but play a critical role in the functioning and maintence of CTL cytotoxic capacity and CTL memory as well. (6) Antigen specific CD8+CTL cloning proliferation and spread in peripheral blood, lymph nodes, and spleen are advanced by cytokines and chemokines such as IL-1 P , IL-8, .macrophage inflammatory protein- 1 Y(MIP-1 Y) secreted by CD154/CD40 signal activated DCs. Moreover,a further enrichment and infiltration of CD8+CTL in tumor tissue has been observed following CD154/CD40 interaction. (7) DCs activated by CD154/CD40 interaction overcome the suppression... |
PDF Full Text Request