Neutrophils sustain pathogenic CD8+ T cell responses in the heart.
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 10(5) 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-gamma and IP-10 mRNA in the myocardium. Neutrophil depletion did not effect survival of CMy-mOva mice that received 3 x 10(6) 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.
Grabie
Nir
N
Immunology Research Division and Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Hsieh
Dennis T
DT
Buono
Chiara
C
Westrich
Jason R
JR
Allen
Jessica A
JA
Pang
Hong
H
Stavrakis
George
G
Lichtman
Andrew H
AH
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000950:Antigens, Ly / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D004527:Egg Proteins / Q000276:immunology; D006321:Heart / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments; D020127:Recovery of Function; D012720:Severity of Illness Index; D013997:Time Factors
D000906:Antibodies; D000950:Antigens, Ly; D004527:Egg Proteins; C480309:Ly6G antigen, mouse; C110366:OVA-8; D010446:Peptide Fragments; D010047:Ovalbumin