Background/Purpose: A lupus-like disease can be induced in B6D2F1 mice by the transfer of parental DBA/2 splenocytes (DBA->F1). Transfer of splenocytes from the other parent (B6->F1) results in B6 anti-F1 CD8 cytotoxic T lymphocytes (CTL) that abort lupus by eliminating host lymphocytes, particularly B cells (acute graft-vs.-host disease)(GVHD). In DBA->F1 mice, donor anti-host CTL fail to develop allowing donor CD4 T cell help to B cells and autoantibody production to proceed unchecked (chronic GVHD).  Depletion of donor CD8 T cells (i.e. transfer of purified CD4 T cells) from either parent results in lupus although renal disease is milder with B6 CD4 T cells.

Methods: To determine whether CD4 T cells exhibit strain-based differences in lupus inducing capacity, disease was induced in B6D2F1 mice following transfer of equal numbers of purified parental CD4 T cells. B10.D2 splenocytes (which behave like B6 splenocytes) were substituted for B6 donors to ensure that both donor populations recognized H-2^b. Because the F1 strain is constant, differences in disease expression can be ascribed to the donor strain.

Results: Long term, DBA CD4->F1 mice exhibited more severe lupus renal disease (histology, proteinuria, mortality) and significantly greater T follicular helper cells (donor and host) and IL-21 gene expression vs. B6 CD4->F1. Short term (< 2 weeks), B6 CD4->F1 mice exhibited greater donor CD4 intracellular IFN-g and TNF and greater host CD8a+ DC expansion vs. DBA CD4->F1 mice however, DBA CD4->F1 mice exhibited significantly greater expansion of plasmacytoid DC and IL-21 gene expression. To address the mechanism of defective DBA CD8 CTL maturation, purified CD4 and CD8 T cells from both donors were matched or mixed prior to transfer. For matched injections, both B10.D2 CD4 +B10.D2 CD8 (D2+D2->F1) mice and DBA+DBA->F1 mice exhibited the expected acute and chronic GVHD phenotype respectively at 2 weeks. For mixed subsets, D2+ DBA->F1 exhibited a phenotype not significantly different from control acute GVHD indicating that normal (D2) CD4 T cell help could correct intrinsic DBA CD8 CTL defects e.g., poor KRLG-1 upregulation.  By contrast, DBA+D2->F1 mice exhibited an intermediate phenotype significantly different from either control group indicating that normal D2 CD8 CTL maturation was significantly impaired with DBA CD4 help. Long term, only DBA+DBA->F1 and DBA+D2->F1 mice exhibited significant lupus autoantibodies or renal disease.

Conclusion:    Following an experimental loss of tolerance, B10.D2 CD4 T cells skew towards a strong Th1 cell mediated immune response that mitigates lupus expression whereas DBA CD4 T cells exhibit weak Th1 skewing but are strongly lupus prone by virtue of: 1) greater help for autoreactive B cells, 2) greater pDC and IL-21 expression, and 3) poorer help for down regulatory CD8 CTL. These data indicate that inherent strain differences in qualitative CD4 T cell responses to the same F1 alloantigens determine lupus expression in this model. Similar qualitative differences in CD4 T cell responses to a lupus trigger in humans could also contribute to disease expression.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inherent-strain-based-differences-in-qualitative-cd4-t-cell-responses-determine-lupus-severity/