This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 101/3/248    most recent CIRCRESAHA.106.147124v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Love, V. A. Articles by Lichtman, A. Search for Related Content PubMed PubMed Citation Articles by Love, V. A. Articles by Lichtman, A. Related Collections Other heart failure Cardiovascular Pharmacology Animal models of human disease Related Article

(Circulation Research. 2007;101:248.)
© 2007 American Heart Association, Inc.

Molecular Medicine

CTLA-4 Ablation and Interleukin-12–Driven Differentiation Synergistically Augment Cardiac Pathogenicity of Cytotoxic T Lymphocytes

Victoria A. Love, Nir Grabie, Paurene Duramad, George Stavrakis, Arlene Sharpe, Andrew Lichtman

From the Vascular Research Division (V.A.L, N.G., P.D., G.S., A.L.), Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School; and Department of Pathology (A.S.), Harvard Medical School, Boston, Mass.

Correspondence to Andrew H. Lichtman, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, 77 Ave Louis Pasteur, NRB 752N, Boston, MA 02115. E-mail alichtman{at}rics.bwh.harvard.edu

CD8⁺ cytotoxic T lymphocytes contribute to viral and autoimmune myocarditis and cardiac allograft rejection. The role of cytotoxic T-lymphocyte–associated antigen (CTLA)-4 as a negative regulator of CD4⁺ T cells is well defined, yet CTLA-4 regulation of CD8⁺ T cells is less clear. We studied CTLA-4 regulation of cytotoxic T lymphocytes in a transgenic model of CD8⁺ T-cell–mediated myocarditis. We generated CTLA-4^–/– Rag 2^–/– OT-1 mice, the CD8⁺ T cells of which express an ovalbumin (OVA) peptide-specific, class I major histocompatibility complex–restricted T-cell receptor. CTLA-4^–/–Tc12 OT-1 effectors, differentiated with interleukin-12 present, are hyperproliferative in vitro, compared with CTLA-4^+/+Tc12 OT-1 controls. Transfer of low doses of CTLA-4^–/–Tc12 OT-1 cells to cMy-mOVA mice, which express OVA on cardiac myocytes, causes severe myocarditis, with 99% mortality, compared with no mortality after transfer of low doses of CTLA-4^+/+Tc12 OT-1 cells. High doses of CTLA-4^+/+Tc12 cells cause lethal myocarditis in cMy-mOVA mice, but high doses of CTLA-4^+/+Tc0 CTL, generated without interleukin-12, are hypoproliferative within the cardiac-draining lymph node and do not significantly infiltrate the heart. In contrast, CTLA-4^–/–Tc0 cytotoxic T lymphocytes do proliferate in the cardiac-draining lymph node and diffusely infiltrate the heart. Nonetheless, high doses of CTLA-4^–/–Tc0 cells cause only limited tissue damage, and the disease is not lethal. These data show that CTLA-4 regulates myocarditic CD8⁺ T cell responses and that CTLA-4 deficiency partly overcomes a differentiation block that exists when naïve CD8⁺ T cells are stimulated without interleukin-12. Therefore, targeting CTLA-4 solely or in conjunction with interleukin-12 could influence effector CD8⁺ T cell responses in therapeutically beneficial ways.

Key Words: rodent • cytotoxic T lymphocytes • CTLA-4 • myocarditis

Related Article:

Crosstalk Between Cytotoxic T-Lymphocyte–Associated Antigen-4 and Interleukin-12 in Cytotoxic T-Lymphocyte–Mediated Myocarditis: Adding Another Link to the Chain

Seema S. Ahuja, Carlos A. Estrada, and Merry L. Lindsey
Circ. Res. 2007 101: 218-220. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				S. S. Ahuja, C. A. Estrada, and M. L. Lindsey Crosstalk Between Cytotoxic T-Lymphocyte Associated Antigen-4 and Interleukin-12 in Cytotoxic T-Lymphocyte Mediated Myocarditis: Adding Another Link to the Chain Circ. Res., August 3, 2007; 101(3): 218 - 220. [Full Text] [PDF]