The Natural History of Disease Expression in CD4 and CD8 Gene-Deleted New Zealand Black (NZB) Mice

CD4 and CD8 gene-deleted New Zealand black (NZB) mice and, as controls, B6.CD4 -/-, B6.CD8 -/-, NZB, and B6 wild-type (wt) mice were studied for phenotypic and immunologie parameters to determine the contribution of CD4 and CD8 cell lineages in NZB mice. These studies suggest surprisingly that a number of abnormalities are not due to either CD4⁺ or CD8⁺ cell lineages but rather are most likely due to non-CD4⁺ and -CD8⁺ cell lineages and/or background genes. Such abnormalities include altered thymic architecture, decreased staining of MTS 33⁺ medullary thymocytes, and an increased frequency of splenic IgM secretory cells. In contrast, deletion of either CD4⁺ or CD8⁺ cells appears to differentially influence immunologie function. Deletion of CD8⁺ cells did not influence titers of spontaneously occurring anti-erythrocyte or anti-DNA autoantibodies. Interestingly, 50% of NZB.CD4 -/- mice contained levels of anti-erythrocyte IgG and anti-ssDNA IgM autoantibodies even without detectable CD4⁺ cells. Such deletion of CD4⁺ cells, while leading to marked decreases in the prototype cytokines that characterize Th1 and Th2 subsets in B6 mice, led to a marked increase in IFN-γ and a moderate increase in IL-4 mRNA levels in NZB.CD4 -/- mice. These data suggest that whereas non-CD4⁺ and -CD8⁺ cell lineages and NZB background genes have a marked influence in the development of autoimmune abnormalities, CD4⁺ cells appear to play a major role in influencing the cytokine environment, whereas CD8⁺ cells appear to play a minor role.