TRANSGENIC MICE EXPRESSING MHC CLASS-II MOLECULES WITH TRUNCATED A(BETA) CYTOPLASMIC DOMAINS REVEAL SIGNALING-INDEPENDENT DEFECTS IN ANTIGEN PRESENTATION

The thymic development and peripheral activation of CD4(+) T cells are critically dependent upon interactions with MHC class II molecules on the surface of antigen presenting cells (APC). In vitro studies invol ving transfection of cell lines with mutant MHC molecules have demonst rated that the cytoplasmic domains of class II molecules can be requir ed for efficient antigen presentation. To address the role of class II cytoplasmic domains in physiological, non-transformed APC and in vivo immune responses, we have generated transgenic mice which express onl y truncated class II A(beta) molecules lacking the 13 membrane distal residues. In vivo, CD4(+) T cell development and immune responses to c onventional protein antigens, parasitic infections and skin grafts wer e indistinguishable between control and transgenic mice. Nevertheless, in vitro, APC from transgenic mice poorly stimulate T cell hybridomas and wild-type in vivo-primed T cells. Neither class II-mediated induc tion of B7-1 expression nor homotypic aggregation were diminished in t ransgenic B cells, suggesting that both cAMP and tyrosine kinase signa ling pathways remain intact despite truncation of the A(beta) cytoplas mic domain. Furthermore, chemically-fixed cells from transgenic animal s are impaired in their antigen presenting capacity. Thus, in contrast to previous studies with cell lines transfected with truncated class II molecules, these results suggest that signaling-independent mechani sms account for the defective in vitro antigen presenting capacity of physiological APC expressing truncated A(beta) proteins.