Pathogenesis of autoimmunity in αβ T cell‐deficient lupus‐prone mice

Murine lupus in MRL mice has been strongly attributed to αβ T cell‐dependent mechanisms. Non‐αβ T cell‐dependent mechanisms, such as γδ T cells, have been shown to drive antibody and autoantibody production, but they have not been considered capable of inducing end‐organ disease. Here, we have expanded upon the findings of such previous work by examining the mechanism and extent of end‐organ disease attainable via γδ T cells and/or non‐αβ T cell‐dependent mechanisms, assessing two prototypical lupus lesions, renal and skin disease, in TCR α−/− MRL mice that possessed either functional or defective Fas antigen (Fas + or lpr ). Observed to 1 year of age, TCR α−/− MRL mice developed disease characterized by increased mortality, overt renal disease and skin lesions. While delayed in onset and/or reduced in severity compared with TCR α+/+ MRL/ lpr animals, renal and skin lesions in αβ T cell‐deficient animals were clearly increased in severity compared with age‐matched control non‐autoimmune mice. In contrast to TCR α+/+ MRL mice, whose disease reflected pan‐isotype immune complex deposition with significant complement fixation, renal disease in TCR α−/− MRL animals reflected predominantly IgG1 immune complex deposition, with poor complement fixation. Thus, this study demonstrates conclusively that non‐αβ T cell‐dependent mechanisms can induce renal and skin injury in murine lupus, but at least in the kidney, only via humoral autoimmunity of a relatively non‐pathological isotype which results in the delayed onset of end‐organ damage.