The deficiency of programmed cell death 1 (PD-1, Pdcd1), a negative immuno-receptor belonging to the CD28/cytotoxic T lymphocyte antigen 4 (CTLA-4) family, can support various tissue-specific autoimmune conditions. Here, we analyzed the effect of PD-1 deficiency in MRL mice that is genetically predisposed to systemic autoimmunity. MRL-Pdcd1-/- mice developed a fatal myocarditis, which is reminiscent of CTLA-4-deficient (Ctla4-/-) mice. Massive infiltration of CD4+ and CD8+ T cells and myeloid cells was found in hearts of MRL-Pdcd1-/- mice concomitant with the production of high-titer auto-antibodies against cardiac myosin. In contrast to Ctla4-/- mice in which most of the CD4+ T cells are non-specifically activated and invade various organs, T cells in the heart but not in the spleen and lymph nodes are activated in MRL-Pdcd1-/- mice, suggesting that myocarditis is mediated by antigen-specific autoimmune response. Heart infiltrating myeloid cells strongly suppressed the allogenic response of T cells in vitro, suggesting that these Mac1+Gr1+ myeloid cells are phenotypically similar to myeloid suppressor cells, which can be found in tumorbearing hosts. These findings unravel the hidden heart-specific autoimmune predisposition of MRL mice and provide MRL-Pdcd1-/- mice as a useful animal model of lymphocytic myocarditis.
ASJC Scopus subject areas
- Immunology and Allergy