Superantigen Sea Induced The Molecular Mechanism Of T Cells Disability

Molecular mechanism of T lymphocytes anergyinduced by superantigen SEAAbstractImmune tolerance is always of importance in the field of immunology and it is also a problem difficult to resolve. Anergy is a major mechanism to ensure antigen-specific tolerance in T lymphocytes in the adult. In recent years, much attention has been paid to the molecular mechanism of T cells anergy.Superantigen is a kind of novel protein antigens which can directly activate a large number of T lymphocytes in a manner of MHC unrestricted~. TCRV specificity. Its unique activation fasion makes it have special biological effects. Leading to T cells anergy and deletion is one of the important biological effects.In an attempt to understand how anergic T cells maintain their unresponsive state, several groups have analyzed the molecular defects in anergic T cell clones. The results suggest that the impaired transcription of the IL-2 gene in anergic T cells is a consequence of a block in TCR-induced activation of p21 Ras and its downstream mitogen- activated protein kinase(MAPK)pathways. It is also called as "Ras-blocked"anergy. In addition, the involvement of AP-1~ NF-kappaB.~ NF-AT~ c-Fos.~ FosB~. JunB~. negative regulatory factors and Rap 1 has been suggested. In the more recently, a study suggest that in vivo SEB-induced anergic state of T cells is established and maintained by a selective impairment in the TCR-induced activation of Calcalcineurin pathway. It is called as"calcium-blocked"anergy because of theaddition of a small amount of calcium ionophore was able to rescue the anergicstate. However how do the upstream events of TCRsignal transductionpathway affect these blocked downstream evenis? As the critical co-stimulators,CD28/CTLA-4, what roles have they played in the induction and maintenenceof T cel1s anergy by superantigen? All of these questiones remain to explore. Inconclusion, the intracellular biochemical basis underlying the induction ofanergy is stiIl Iargely unknown. To resolve these (' source" questiones is criticalfor the clarification of immune tolerance.Superantigen can activate a large number of T lymphocytes and interactwith T cells in a manner of MHC unstricted, which make the establishmemt ofT cells anergy model induced by superantigen in vitro possible. lt is the firsttime to establish a T cell anergy model and to study the molecular mechanismof T cells anergy ihduced by superantigen SEA in vitro. The experimentalcontents and results are mainly as fOllows:l. Activation of peripheral bIood T cells stimulated by superantigenSEA.Native T cells exposed saperantigen induce a strong proliferative response.After the initial phase of superantigen~induced activation, part of the reactive Tcells are deleted and the remaining T-cell population fails to proliferate andsecrete IL-2 in response to a subsequellt superamigen chal1enge. So in order toinvestigate the mechanism of T cells anergy induced by superaatigen, first ofal1 is to explore the activation of T cells induced by superantigen.StaPhylococcal enterotoxin A is a kind of exotoxins secreted bystaPhyococcus aureus and it is the best-characterized kind of SEs. ln ourexperiments we have investigated the activation properties of PBMC bysuperanigen SEA. OIt is suggested that l0~l04 ng/mL is the optimal SEAconcentration range to activate T cells in vitro by using 3H-TdR incorperationassay. @That the activation arrives at top at the 2. 3 days after the addition ofVISEA analyzed by ELISA. @SEA activates the CD4+ and CD8+T subPopulatioasin the same degree without changing the phenotyPe of CD4/CD8 in the first SEAstirnulation or the restimulation tbrough FACS analySis.2. EstabIi8hment of T cells anergy model induced by superantigenSEA in vitro.We have to establish a suitable T cells anergy model in prior to investigatethe molecular mechanism of T cells anergy. So we have conducted thefOllowing works: OThe short-time resting SEA-reactive T cells l...