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(American Journal of Pathology. 2003;163:2413-2420.)
© 2003 American Society for Investigative Pathology

Neutrophils Sustain Pathogenic CD8⁺ T Cell Responses in the Heart

From the Immunology Research Division and Vascular Research Division, Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts

Correspondence: Address correspondence to Andrew H. Lichtman, M.D., Ph.D., Department of Pathology, Brigham and Women’s Hospital, HIM/NR87, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail: alichtman{at}rics.bwh.harvard.edu

This study explores the influence of innate immunity on CD8⁺ T-cell responses against heart tissue. Adoptive transfer of ovalbumin-specific CD8⁺ effector T cells into CMy-mOva mice, which express ovalbumin in cardiac myocytes, results in a lethal acute myocarditis. The inflammatory infiltrate in the heart includes neutrophils as well as T cells. We used anti-Ly6G antibody to transiently deplete neutrophils at the time of onset of disease. By day 7 after receiving 5 x 10⁵ CD8⁺ effector T cells, 100% of control Ig-treated CMy-mOva mice had died, while 85% of anti-Ly6G-treated mice survived indefinitely. CD8⁺ T-cell infiltration and tissue damage were present in both groups, but the disease was limited in the anti-Ly6G-treated mice, with a rapid disappearance of the adoptively transferred CD8⁺ T cells within 11 days. Recovery occurred even though blood neutrophil counts began to rise 48 hours after the last anti-Ly6G treatment. Recovery was associated with a chronic CD4⁺ cell infiltrate, and a rapid decline in expression of IFN- and IP-10 mRNA in the myocardium. Neutrophil depletion did not effect survival of CMy-mOva mice that received 3 x 10⁶ CD8⁺ T cells. These data show that granulocytic inflammation sustains CD8⁺ T-cell-mediated heart disease, which has important implications for the pathogenesis and treatment of acute myocarditis and allograft rejection.

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