Functional analysis of peripheral tolerance

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1)Signals generated by TCR slimulation alone is not sufficient to activate IL2 gene and thus induces anergy in resting T cells. We found that TCR stimulation alone induces activation of MAPK/ERK but not SAPK/JNK and p38/CSBP.When T cells were stimulated through both TCR and CD28, all three MAPK superfamily members were activated.2)SAPK/JNK and p38/CSBP pathways form redundant pathways and MAPK/ERK pathway syuergistically functions with SAPK/JNK and p38/CSBP pathways in activation of IL2 gene.3)Activation of SAPK/JNK and p38/CSBP pathways but not MAPK/ERK pathway are sensitive to cyclosporin A.Activation of SAPK/JNK and p38/CSBP pathways by osmotic shock is not inhibited by cyclosporin A, suggesting the existence of a cyclosporin A sensitive step between TCR/CD28 and activation of SAPK/JNK and p38/CSBP pathways.4)When peripheral T cells from HY/rag-2^% mice specific for a male antigen HY in the presence of H-2D^b were injected into male B6-Ly5.2-rag-2^% mice, donor derived cells were activated and increased in the recipient body. But after a while the cell numbers decreased to an undetectable level. In contrast, when peripheral T cells from HY/lpr/rag-2^% mice were used, such decrease in cell numbers was not observed because of the lack of Fas/FasL induced cell death. Instead, cell numbers increased and eventually reached a plateau level. Such cells do not respond to antigen in vitro but they restore the reactivity against antigen after transfer into female mice.We are planning to isolate such "in vivo induced anergic cells" and analyze their characteristics such as surface phenotype and signal transduction machinery downstream of the TCR.