Whereas most CD8 + T cells in lymph nodes and spleen express the CD8 § g heterodimer and depend absolutely on thymic competence for their development, a substantial population of T cells expressing CD8 § § matures extrathymically. Although the existence of these CD8 sublineages is well established, relatively little is known about differences that might exist among CD8 cells in their requirement for particular transcriptional pathways during the development and maintenance of normal populations. Transgenic mice whose T lineage expresses an I O B § mutant exhibited decreased NF-O B signaling and a diminution in mature CD8 T cells. We now have determined that although TCR-dependent CD69 induction by CD8 § § and CD8 § g T cells was unaffected by inhibition of NF-O B, TCR § g CD8 § g T cells were preferentially reduced compared to their TCR § g CD8 § § or TCR + ˇ counterparts. This finding was most prominent in spleen, but was also apparent in Peyer's patches of trans-genic mice. In addition, diminished antiviral cytotoxic responses of CD8 § g intraepithelial lymphocytes were observed after enteric reovirus infection. Taken together, these results indicate that NF-O B signaling is more important for the thymus-dependent TCR § g CD8 § g population than for other CD8 lineages, and thus regulates the number, function, and normal balance of CD8 subsets in the periphery.