We also showed that previously exposed NK cells were essential to confer significant protection against secondary HSV-2 infection induced morbidity and mortality and this protection was specific for HSV-2 infection. It has been shown that NK cells can remember past encounters of chemical haptens, activation by cytokines and MCMV. This finding suggests that cytokines may be playing a role in the activation of NK cells. The previous observations and the current findings suggest that the length of remembrance of Ags by NK cells vary depending on the encountered Ags or possibly the presence of T cells in the environment. The latter view could be supported by the finding that human NK cells can proliferate and increase the activity in an Ag specific manner for several months against rabies viral Ags with helper signals from memory CD4 cells and accessory cells such as macrophages. It has long been accepted that immunoglobulins can only be expressed in mature B lymphocytes and plasma cells. However, recently several groups reported that Igs could also be produced by non-lymphoid lineage cells, including human cancer cells, soft tissue tumor cells, neurons and glial cells of the central and peripheral nervous system, ocular epithelial and ganglion cells, mouse testicular spermatogenic cells and epididymal epithelial cells and mouse lactating mammary gland epithelial cells. Most of the research has thus far focused on Ig expression in cancer cells. The Recombination activating gene has also been found expressed in cancer cells both at the mRNA and the protein levels and it is assumed to play a significant role in the synthesis of Igs by these cancer cells. However, the regulatory mechanism of RAG expression in cancer cells has not yet been determined. The variable regions of Ig genes are composed of one variable, one diversity, and one joining gene segment, the arrangement of which results from V J recombination. RAG endonuclease is required for the initiation of the cleavage phase of V J recombination. RAG consists of two adjacent genes, RAG1 and RAG2, that synergistically induce V J recombination. Previous studies have shown that mice deficient in either RAG1 or RAG2 failed to initiate V J rearrangement. RAG1 and RAG2 proteins together were found to be sufficient to Protopanaxtriol cleave recombination substrates in cell free systems. In murine B cell development RAG expression occurs in two waves and is regulated by a network of transcription factors, including E2A, Ikaros, Pax5b, Foxo1, Foxp1, and NF-kB. The first wave results in the rearrangement of the immunoglobulin heavy chain in pro-B cells. And the second wave of RAG expression leads to the assembly of immunoglobulin light chain in pre-B cells. In addition to the RAG1 and RAG2 promoters, the RAG gene has also other regulatory elements, such as the proximal enhancer, the distal enhancer and the RAG enhancer. It is thought that the aforementioned transcription factors regulate RAG expression by Quinine hydrochloride Dihydrate binding to their corresponding regulatory sequences in B cells. Erag is the strongest enhancer regulating RAG expression. Targeted deletion of Erag in the mouse germline resulted in a 5-fold to 10-fold decrease in RAG expression and a partial block at the pro-B to pre-B transition. E2A, Ikaros, Foxo1, Foxp1 and NF-kB were all shown to activate RAG expression by binding to Erag in murine B cells. Pax5b was reported to activate RAG2 promoter in immature B cells.