Lymphocyte programmed cell death is mediated via HLA class II DR

HLA class II molecules are constitutively expressed on human B lymphocytes and are induced on human T lymphocytes after activation, through which signal transduction via these molecules has been extensively described. We have observed cell death of as many as 60% after stimulation of lymphocytes via HLA class II DR molecules, but not via DP or DQ. Propidium iodide fluorescence, DNA fragmentation and morphology of the dead cells were examined. The reported cell death was very rapid, and independent of Fc receptors and of complement. A morphologically distinct sub-population of activated B cells was sensitive to HLA-DR mediated death, while resting B lymphocytes from the same donor did not die as a result of HLA class II mediated stimulation. Death via HLA-DR was distinguishable from necrosis. Cytoskeletal integrity, serine/threonine phosphatase activity and endonucleases were required for the pathway leading to HLA-DR mediated death. The 'ladder' pattern of DNA fragmentation which typically characterizes apoptosis was not observed, despite the observation of cell and nuclear shrinkage normally associated with apoptosis. These data suggest that HLA class II mediated death is a means of rapidly removing either T or B lymphocytes which have already served their role in the immune response, thereby avoiding the inflammatory responses associated with necrosis and concentrating the ligands for new TCR and/or CD4 interactions.