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 involving transfection of cell lines with mutant MHC molecules have demonstrated that the cytoplasmic domains of class II molecules can be required 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 only truncated class II A beta molecules lacking the 13 membrane distal residues. In vivo, CD4+ T cell development and immune responses to conventional protein antigens, parasitic infections and skin grafts were 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 induction of B7-1 expression nor homotypic aggregation were diminished in transgenic B cells, suggesting that both cAMP and tyrosine kinase signaling pathways remain intact despite truncation of the A beta cytoplasmic domain. Furthermore, chemically-fixed cells from transgenic animals 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 mechanisms account for the defective in vitro antigen presenting capacity of physiological APC expressing truncated A beta proteins.
Smiley
S T
ST
Department of Cancer Biology, Harvard School of Public Health, Boston, MA 02115, USA.
Laufer
T M
TM
Lo
D
D
Glimcher
L H
LH
Grusby
M J
MJ
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D003593:Cytoplasm / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000276:immunology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics*; D019076:Transgenes / Q000276:immunology
D000949:Histocompatibility Antigens Class II; D010455:Peptides