Transgenic Mice Expressing Functional TCRs Specific to Cardiac Myhc-α 334-352 on Both CD4 and CD8 T Cells Are Resistant to the Development of Myocarditis on C57BL/6 Genetic Background

  • Cells. 2023 Sep 25;12(19):2346. doi: 10.3390/cells12192346.
Meghna Sur  1 ,  Mahima T Rasquinha  1 ,  Rajkumar Arumugam  1  2 ,  Chandirasegaran Massilamany  1  3 ,  Arunkumar Gangaplara  1  4 ,  Kiruthiga Mone  1 ,  Ninaad Lasrado  1  5 ,  Bharathi Yalaka  1  2 ,  Aakash Doiphode  1  6 ,  Channabasavaiah Gurumurthy  7 ,  David Steffen  1 ,  Jay Reddy  1
Affiliations
  • 1. School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
  • 2. Bristol Myers Squibb, Summit, NJ 07901, USA.
  • 3. CRISPR Therapeutics, Boston, MA 02127, USA.
  • 4. Miltenyi Biotec, Gaithersburg, MD 20878, USA.
  • 5. Center for Virology and Vaccine Research, Harvard Medical School, Boston, MA 02115, USA.
  • 6. Department of Animal Genetics and Breeding, Krantisinh Nana Patil College of Veterinary Science, Shirwal 412801, Maharashtra, India.
  • 7. Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
PMID: 37830560 DOI: 10.3390/cells12192346
Abstract

Myocarditis is a predominant cause of congestive heart failure and sudden death in children and young adolescents that can lead to dilated cardiomyopathy. Lymphocytic myocarditis mediated by T cells can result from the recognition of cardiac antigens that may involve CD4 or CD8 T cells or both. In this report, we describe the generation of T cell receptor (TCR) transgenic mice on a C57BL/6 genetic background specific to cardiac Myosin heavy chain (Myhc)-α 334-352 and make the following observations: First, we verified that Myhc-α 334-352 was immunogenic in wild-type C57BL/6 mice and induced antigen-specific CD4 T cell responses despite being a poor binder of IAb; however, the immunized Animals developed only mild myocarditis. Second, TCRs specific to Myhc-α 334-352 in transgenic mice were expressed in both CD4 and CD8 T cells, suggesting that the expression of epitope-specific TCR is common to both cell types. Third, although T cells from naïve transgenic mice did not respond to Myhc-α 334-352, both CD4 and CD8 T cells from Animals immunized with Myhc-α 334-352 responded to the peptide, indicating that antigen priming is necessary to break tolerance. Fourth, although the transgenic T cells could produce significant amounts of interferon-γ and interleukin-17, the immunized Animals developed only mild disease, indicating that Other soluble factors might be necessary for developing severe myocarditis. Alternatively, the C57BL/6 genetic background might be a major contributing factor for resistance to the development of myocarditis. Taken together, our model permits the determination of the roles of both CD4 and CD8 T cells to understand the disease-resistance mechanisms of myocarditis in a single transgenic system antigen-specifically.

Keywords
TCR transgenic mice; cardiac myosin-α 334–352; inflammatory cardiomyopathy; myocarditis.
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