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Given the promising results in human lupus with B cell depletion, we tested whether in vivo cytotoxic T lymphocyte (CTL) could eliminate autoreactive B cells in the setting of murine lupus. Using the parent-into-F1 (P → F1) model to generate CTL that eliminate B cells, we found that transfer ofNZB parental splenocytes into lupus-prone female NZB/W F1 mice resulted in profound B cell reduction whereas NZW → F1 mice exhibited defective B cell elimination. Using pre-disease or early disease B/W mice as hosts, NZB → F1 mice exhibited B cell depletion and improved proteinuria but no improvement in survival whereas NZW → F1 mice had significantly reduced proteinuria and prolonged survival. Thus, despite the defective IL-2 environment in B/W F1 mice, generation of CTL and B cell depletion is feasible in NZB → F1 mice. The surprising increase in survival for NZW → F1 mice despite defective B cell elimination suggests that NZW splenocytes may contain a beneficial down regulatory cell., (Published by Elsevier Inc.)

To test the relative roles of perforin (pfp) vs. FasL in CTL control of autoreactive B cell expansion, we used the parent-into-F1 model of murine graft-vs.-host disease in which donor CD8 CTL prevent lupus like disease by eliminating activated autoreactive B cells. F1 mice receiving either pfp or FasL defective donor T cells exhibited an intermediate short-term phenotype. Pairing of purified normal CD4 T cells with either pfp or FasL defective CD8 T cell subsets resulted in impaired host B cell elimination and mild lupus like disease that was roughly equivalent in the two experimental groups. Thus, in addition to major roles in tumor and intracellular pathogen control, pfp mediated CD8 CTL killing plays a significant role in controlling autoreactive B cell expansion and lupus downregulation that is comparable to that mediated by FasL killing. Importantly, both pathways are required for optimal elimination of activated autoreactive B cells., (Published by Elsevier Inc.)

Using the parent-into-F1 model of induced lupus and (C57BL/6 × DBA2) F1 mice as hosts, we compared the inherent lupus-inducing properties of the two parental strain CD4 T cells. To control for donor CD4 recognition of alloantigen, we used H-2(d) identical DBA/2 and B10.D2 donor T cells. We demonstrate that these two normal, nonlupus-prone parental strains exhibit two different T cell activation pathways in vivo. B10.D2 CD4 T cells induce a strong Th1/CMI pathway that is characterized by IL-2/IFN-γ expression, help for CD8 CTLs, and skewing of dendritic cell (DC) subsets toward CD8a DCs, coupled with reduced CD4 T follicular helper cells and transient B cell help. In contrast, DBA/2 CD4 T cells exhibit a reciprocal, lupus-inducing pathway that is characterized by poor IL-2/IFN-γ expression, poor help for CD8 CTLs, and skewing of DC subsets toward plasmacytoid DCs, coupled with greater CD4 T follicular helper cells, prolonged B cell activation, autoantibody formation, and lupus-like renal disease. Additionally, two distinct in vivo splenic gene-expression signatures were induced. In vitro analysis of TCR signaling revealed defective DBA CD4 T cell induction of NF-κB, reduced degradation of IκBα, and increased expression of the NF-κB regulator A20. Thus, attenuated NF-κB signaling may lead to diminished IL-2 production by DBA CD4 T cells. These results indicate that intrinsic differences in donor CD4 IL-2 production and subsequent immune skewing could contribute to lupus susceptibility in humans. Therapeutic efforts to skew immune function away from excessive help for B cells and toward help for CTLs may be beneficial., (Copyright © 2015 by The American Association of Immunologists, Inc.)