GENERATION OF MUCOSAL CYTOTOXIC T-CELLS AGAINST SOLUBLE-PROTEIN BY TISSUE-SPECIFIC ENVIRONMENTAL AND COSTIMULATORY SIGNALS

We compared peripheral and mucosal primary CD8 T cell responses to inf lammatory and noninflammatory forms of antigen in a T cell-adoptive tr ansfer system, Immunization with the soluble antigen, ovalbumin (ova), administered i.p. or orally without adjuvant, activated nonmucosal CD 8 T cells but did not induce cytotoxic activity. However, after activa tion, the transferred cells entered the intestinal mucosa and became p otent antigen-specific killers. Thus, exogenous intact soluble protein entered the major histocompatibility complex class I antigen presenta tion pathway and induced mucosal cytotoxic T lymphocytes. Moreover, di stinct costimulatory requirements for activation of peripheral versus mucosal T cells were noted in that the CD28 ligand, B7-1, was critical for activated mucosal T cell generation but not for activation of per ipheral CD8 T cells, The costimulator, B7-2, was required for optimum activation of both populations, Infection with a new recombinant vesic ular stomatitis virus encoding ovalbumin induced lytic activity in muc osal as well as peripheral sites, demonstrating an adjuvant effect of inflammatory mediators produced during virus infection. Generation of antiviral cytotoxic T lymphocytes was also costimulation-dependent. Th e results indicated that induction of peripheral tolerance via antigen administration may not extend to mucosal sites because of distinct co stimulatory and inflammatory signals in the mucosa.