IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis
Nir Grabie, Michael W. Delfs, Jason R. Westrich, Victoria A. Love, George Stavrakis, Ferhaan Ahmad, Christine E. Seidman, Jonathan G. Seidman, Andrew H. Lichtman
Nir Grabie, Michael W. Delfs, Jason R. Westrich, Victoria A. Love, George Stavrakis, Ferhaan Ahmad, Christine E. Seidman, Jonathan G. Seidman, Andrew H. Lichtman
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Article Autoimmunity

IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis

Abstract

Cardiac antigen–specific CD8+ T cells are involved in the autoimmune component of human myocarditis. Here, we studied the differentiation and migration of pathogenic CD8+ T cell effector cells in a new mouse model of autoimmune myocarditis. A transgenic mouse line was derived that expresses cardiac myocyte restricted membrane-bound ovalbumin (CMy-mOva). The endogenous adaptive immune system of CMy-mOva mice displays tolerance to ovalbumin. Adoptive transfer of naive CD8+ T cells from the ovalbumin-specific T cell receptor–transgenic (TCR-transgenic) OT-I strain induces myocarditis in CMy-mOva mice only after subsequent inoculation with ovalbumin-expressing vesicular stomatitis virus (VSV-Ova). OT-I effector T cells derived in vitro in the presence or absence of IL-12 were adoptively transferred into CMy-mOva mice, and the consequences were compared. Although IL-12 was not required for the generation of cytolytic and IFN-γ–producing effector T cells, only effectors primed in the presence of IL-12 infiltrated CMy-mOva hearts in significant numbers, causing lethal myocarditis. Furthermore, analysis of OT-I effectors collected from a mediastinal draining lymph node indicated that only effectors primed in vitro in the presence of IL-12 proliferated in vivo. These data demonstrate the importance of IL-12 in the differentiation of pathogenic CD8+ T cells that can cause myocarditis.

Authors

Nir Grabie, Michael W. Delfs, Jason R. Westrich, Victoria A. Love, George Stavrakis, Ferhaan Ahmad, Christine E. Seidman, Jonathan G. Seidman, Andrew H. Lichtman

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OT-I T-cell–mediated myocarditis in CMy-mOva mice. (a) Mice were injecte...
OT-I T-cell–mediated myocarditis in CMy-mOva mice. (a) Mice were injected with indicated numbers of OT-I0 or OT-IIL-12 effector T cells, whose phenotypes are described in Figure 2, or with OT-IIL-12 cells differentiated in the presence of C57BL/6 STAT-4–/– splenic APCs. Mean survival is shown for each group. Data represent means ± SD (n = 4 per group). Additional studies with more than 16 mice confirmed that CMy-mOva mice survived longer than 72 days after adoptive transfer of 5 × 106 OT-I0. (b) Hearts were harvested 72 hours after adoptive transfer of 106 OT-I effector T cell populations (described in Figure 2). Low- and high-power photomicrographs of hematoxylin- and eosin-stained sections and immunohistochemical stains for CD90.1 (Thy 1.1), which specifically marks the OT-I cells, are shown.