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

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-gamma-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.

Beta-galactoside alpha2,3-sialyltransferase-I gene expression during Th2 but not Th1 differentiation: implications for core2-glycan formation on cell surface proteins.

Biosynthesis of core2 O-glycans on T cell surface glycoproteins is essential for their interactions with selectins expressed by activated endothelium, and may also regulate susceptibility to apoptosis. Beta-galactoside alpha2,3-sialyltransferase-I (ST3Gal-I) is a major inhibitor of core2 O-glycan formation on CD43 and CD45 in naive T cells. Here we show that ST3Gal-I mRNA is extensively expressed during Th2, but not Th1 differentiation. Consistent with this, developing Th1 cells display the non-sialylated core1 galactose (Gal1-3GalNAc-Ser/Thr) and strongly react with peanut agglutinin, while Th2 cells do not. These Th subset differences are also associated with greater expression of the high molecular glycoform of CD43 on the surface of Th1 cells compared with Th2 cells, and similar differences in surface expression of sialyl Lewis-X. We suggest that lack of ST3Gal-I expression in Th1 cells allows the formation of surface core2 O-glycans and supports their interactions with endothelial selectins.