IL-12 is required for differentiation of pathogenic CD8+ T cell effectors that cause myocarditis
Nir Grabie, … , Jonathan G. Seidman, Andrew H. Lichtman
Nir Grabie, … , Jonathan G. Seidman, Andrew H. Lichtman
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):671-680. https://doi.org/10.1172/JCI16867.
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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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Figure 5

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In vivo migration and proliferation of OT-I effector cells. (a) Hematoxy...
In vivo migration and proliferation of OT-I effector cells. (a) Hematoxylin- and eosin-stained sections were prepared from hearts harvested at 48 hours after T cell transfer of 2.5 × 106 OT-I0 or OT-IIL-12 effector cells. (b) Enlarged peribronchial lymph nodes, consistently found in the illustrated location in CMy-mOva mice with myocarditis, were harvested 48 hours after adoptive transfer of 2.5 × 106 OT-I0 or OT-IIL-12 effectors, and FACS analysis was performed as described in Methods. (c) CFSE-labeled OT-I effector cells were transferred into CMy-mOva mice, and peribronchial lymph nodes were harvested after 72 hours for flow cytometric analysis. The histograms show CFSE fluorescence intensity in Thy 1.1+–gated cells. The horizontal bars indicate the range of fluorescence intensity detected in effector cells immediately after labeling, before transfer. (d) The histological grade of myocarditis was assessed, as described in Methods, in hearts harvested at various times after adoptive transfer of 3 × 106 OT-I effectors.