BYSTANDER ACTIVATION OF CYTOTOXIC T-CELLS - STUDIES ON THE MECHANISM AND EVALUATION OF IN-VIVO SIGNIFICANCE IN A TRANSGENIC MOUSE MODEL

Bystander activation, i.e., activation of T cells specific for an anti gen X during an immune response against antigen Y may occur during vir al infections. However, the low frequency of bystander-activated T cel ls has rendered it difficult to define the mechanisms and possible in vivo relevance of this nonspecific activation. This study uses transge nic mice expressing a major histocompatibility complex class I-restric ted TCR specific for glycoprotein peptide 33-41 of lymphocytic choriom eningitis virus (LCMV) to overcome this Limitation. CD8(+) T cells fro m specific pathogen-free maintained, unimmunized ''naive'' TCR transge nic mice can differentiate into LCMV-specific cytolytic effector CTL d uring infections with vaccinia virus or Listeria monocytogenes in vivo or mixed lymphocyte culture in vitro. We show that in these model sit uations (a) nonspecifically activated CTL are able to confer antiviral protection in vivo, (b) bystander activation is largely independent o f the expression of a second T cell receptor of different specificity, (c) bystander activation is not mediated by a broadly cross-reactive TCR, but rather by cytokines, (d) bystander activation can be mediated by cytokines such as IL-2, but not alpha/beta-IFN in vitro; (e) bysta nder activation is, overall, a rare event, occuring in vivo in roughly 1 in 200 of the LCMV-specific CTL during infection of TCR transgenic mice with vaccinia virus; (f) bystander activation does not have a sig nificant functional impact on nontransgenic CTL memory under the condi tions tested; and (g) even in the TCR transgenic situation, where unph ysiologically high numbers of T cells of a single specificity are pres ent, bystander activation is not sufficient to cause clinically manife st autoimmune disease in a transgenic mouse model of diabetes. We conc lude that although bystander activation via cytokines may generate cyt olytically active CTL from naive precursors, quantitative consideratio ns suggest that this is usually not of major biological consequence.