Mice homozygous for lpr and gld develop profound lymphadenopathy characterized by the accumulation of two functionally impaired t cell subsets, a predominant B220+ CD4- CD8- (DN) population and a minor CD4+B220+ subset. Previous studies of diseased lpr and gld mice revealed that enlarged LN also contain elevated numbers of conventional T and B cells and an increased proportion of memory-like CD4+ B220- T cells. In the past year we have continued to explore the effects of lpr and gld on T cell selection, growth and activation. These studies revealed that primed CD4+ and CD8+ T cells are detected in increased numbers in lpr LN by 4 wk of age and accumulate progressively thereafter. Two types of memory cells distinguished by differences in ontogeny, phenotype and the spectrum of cytokines secreted post-stimulation were identified. Examination of TcR Vbeta gene utilization revealed no skewing of the Vbeta repertoire that would implicate autoantigens as a primary stimulus for the activation of CD4+ or CD8+ T cells early or late in disease. The pattern of expression of CD69 on B220+ DN T cells provided further evidence that these cells may be chronically stimulated in vivo but unable to progress through the cell cycle. The functional anergy of DN T cells was reversed by cross-linking TcR alpha/beta and CD28 in the presence of PMA, indicating that the blockage in signal transduction via the TcR complex can be overcome in the presence of a strong costimulatory signal. One unifying hypothesis to explain lymphoproliferative disease is that the lpr and gld mutations result in defective regulation of the size of the pool of primed T and B cells. DN T cells may arise from chronically stimulated, abnormally long- lived CD4+ and CD8+ cells that down-regulate the expression of CD4, CD8 and TcR alpha/beta, switch to the B220 isoform of CD45, and become resistant to activation. Selective accumulation of DN T cells may result from a combination of events including chronic low level stimulation, increased lifespan and the ready availability of growth factors. Experiments to test these predictions are in progress and are outlined.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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Division of Cancer Biology and Diagnosis
United States
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