PD-1 deficiency results in the development of fatal myocarditis in MRL mice

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.