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 tumor-bearing 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.
Wang
Jian
J
Department of Immunology and Genomic Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Japan.
Okazaki
Il-Mi
IM
Yoshida
Taku
T
Chikuma
Shunsuke
S
Kato
Yu
Y
Nakaki
Fumio
F
Hiai
Hiroshi
H
Honjo
Tasuku
T
Okazaki
Taku
T
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D001323:Autoantibodies / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen; D024722:Cardiac Myosins / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance; D007249:Inflammation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D009205:Myocarditis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009928:Organ Specificity; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001323:Autoantibodies; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D024722:Cardiac Myosins