Evidence for major alterations in the thymocyte subpopulations in murine models of autoimmune diseases

Abstract

Thymocytes can be divided into four major subpopulations: CD4 +CD8 + (double-positive), CD4 −CD8 − (double-negative), CD4 +CD8 − (CD4 +) and CD4 −CD8 + (CD8 +) cells. Recent studies have shown that T-cell development in the thymus progresses as: CD4 −CD8 − → CD4 +CD8 + → CD4 + or CD8 + cells. In the present study we investigated these and other subpopulations of thymocytes in autoimmune MRL-+/+, MRL- lpr lpr , C57BL 6 - lpr lpr , BXSB and NZB mice before (1-month old) and after (4–6-months old) the onset of lymphadenopathy and autoimmune disease. All the autoimmune strains at one month of age and other H-2, sex and age-matched controls (C3H, DBA 2 , and C57BL 6 ) demonstrated normal proportions of thymocyte subsets with ∼75% double-positive cells, 5–7% double-negative cells, 11–15% CD4 + cells and 3–5% CD8 + cells. By 4–6 months of age, MRL-+/+ mice demonstrated a moderate increase in double-negative cells (∼13%) and a decrease in double-positive cells (∼46%). Interestingly, in the presence of the lpr gene, as seen in MRL- lpr lpr mice, the double-negative cells increased to ∼47% and the double-positive cells decreased to ∼16%. In contrast, 4–6-month-old C57BL 6 - lpr lpr mice failed to demonstrate any alterations in the thymocyte subsets thereby suggesting that background genes, in addition to the lpr gene, played a role in the thymocyte differentiation. BXSB male mice with severe lymphadenopathy behaved very similarly to MRL- lpr lpr mice, inasmuch as their thymus contained ∼48% double-negative cells and only ∼8% double-positive cells. In contrast to MRL- lpr lpr and BXSB strains, NZB mice at 6 or 10 months of age had normal composition of thymocyte subsets. In MRL and BXSB animals, although there was a significant increase in CD4 + cells (∼23–33%), due to a consequent increase in CD8 + cells (∼11%), the ratio of CD4 +:CD8 + cells remained 2–3:1, similar to that seen in normal mice. Furthermore, using the J11d marker expressed by the majority of the double-negative and all double-positive thymocytes but not by mature functional T cells, we confirmed the above findings and demonstrated further that MRL- lpr lpr mice at 4–6 months of age had an increased percentage of J11d − double-negative cells and a decrease in J11d + double-negative cells. The present study demonstrates for the first time the existence of a common defect in T-cell differentiation in the thymus of autoimmune strains of mice which is dependent on the genetic background and other accelerating factors responsible for inducing autoimmune disease.