Programmed Cell Death-1 Pathway Deficiency Enhances Autoimmunity Leading to Dacryoadenitis of Mice

Abstract

Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti–PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene–knockout (Pdcd1−/−) mice. Histopathologic analysis showed that Pdcd1−/− mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3+ T cells and only a small proportion of CD19+ B cells. Among infiltrating T cells, the CD4+ Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1−/− mice. Experiments of lymphocyte transfer from Pdcd1−/− into irradiated wild-type mice confirmed that CD4+ T cells from Pdcd1−/− mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4+ Th1 cells. Programmed cell death protein (PD)-1 is a coinhibitory molecule that suppresses immune response and maintains immune homeostasis. Moreover, the PD-1 pathway blocks cancers from being attacked by immune cells. Anti–PD-1 antibody therapy such as nivolumab improves survival in cancer patients. However, the occurrence of autoimmune inflammatory disorders in various organs has been increasingly reported as an adverse effect of nivolumab. Of the disorders associated with nivolumab, Sicca syndrome occurs in 3% to 11% of cases and has unknown pathologic mechanisms. Whether the absence of the PD-1 pathway causes functional and morphologic disorders in lacrimal glands was determined by analyzing PD-1 gene–knockout (Pdcd1−/−) mice. Histopathologic analysis showed that Pdcd1−/− mice developed dacryoadenitis beginning at 3 to 4 months of age, and deteriorated with age. Flow-cytometric analysis confirmed that cells infiltrating the affected lacrimal glands consisted mainly of CD3+ T cells and only a small proportion of CD19+ B cells. Among infiltrating T cells, the CD4+ Th-cell subset consisted of Th1 cells producing interferon-γ in an early stage of dacryoadenitis in Pdcd1−/− mice. Experiments of lymphocyte transfer from Pdcd1−/− into irradiated wild-type mice confirmed that CD4+ T cells from Pdcd1−/− mice induced dacryoadenitis. These results indicate that PD-1 plays an important role in the prevention of autoimmune inflammatory disorders in lacrimal glands caused by activated CD4+ Th1 cells. Coinhibitory molecules, such as cytotoxic T lymphocyte–associated antigen (CTLA)-4, B- and T-lymphocyte attenuator (BTLA), and programmed cell death (PD)-1 protein, negatively drive T cell–mediated immune response and maintain immune homeostasis.1Sharpe A.H. Freeman G.J. The B7-CD28 superfamily.Nat Rev Immunol. 2002; 2: 116-126Crossref PubMed Scopus (1355) Google Scholar,2Chen L. 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Development of autoimmune by of the PD-1 gene an 11: Full Text Full Text PDF PubMed Scopus Google Scholar and autoimmune H. Okazaki T. Y. K. M. A. S. A. H. N. Honjo T. in PD-1 2001; PubMed Scopus Google Scholar In of the gene PD-1 protein is associated with a of and an inhibitory effect of PD-1 in the of M. I. J.A. A. of the functional of a regulatory of associated with 2008; PubMed Scopus Google L. Chan M. of is associated with in Rheum. PubMed Scopus Google Scholar Moreover, in tumor the ligand pathway blocks cancers from being attacked by immune cells. mechanism leads to tumor immune including such as nivolumab and and such as an in cancer These immune the survival in with A. CTLA-4 and PD-1 and of PubMed Scopus Google L.M. M. immune and associated Rev PubMed Scopus Google Scholar immune that the immune been associated with number of that are nivolumab for the of cancers develop autoimmune inflammatory disorders in various organs, to as adverse R. adverse associated with immune Med. PubMed Scopus Google M. R. and disease in cancer with immune PubMed Scopus Google Scholar adverse associated with nivolumab and A. CTLA-4 and PD-1 and of PubMed Scopus Google Scholar Sicca syndrome 3% to 11% of the adverse associated with L.M. M. immune and associated Rev PubMed Scopus Google Scholar with adverse of syndrome with salivary However, an of antibody has been L.M. M. immune and associated Rev PubMed Scopus Google A.N. J. J. D. and syndrome induced by nivolumab and PubMed Scopus Google Scholar The mechanism of syndrome as a adverse syndrome is of the autoimmune that In in lacrimal glands and salivary glands results in and N. R. PubMed Scopus Google Scholar The of syndrome clinical including an of lacrimal and salivary a salivary and for autoantibodies including and protein in the The by the of CD4+ and T cells, B cells, natural killer T cells, macrophages, and are in H. of in the and mouse for a role for cells in the of 2000; PubMed Scopus Google cell molecule and 4 and in lymphocyte in syndrome and PubMed Scopus Google of analysis of Google D. D. of in the associated with autoimmune 2002; Google M. in the and of Rev PubMed Scopus Google Scholar In the Pdcd1−/− mice to the absence of the PD-1 pathway immune in and the and in of and mice to as and Pdcd1−/− mice from and by the of and the to the in the for in and for of in and and to a with H. M. Y. T cell role of in a mouse for 2004; Full Text Full Text PDF PubMed Scopus Google Scholar In the mice with an of and was to and production was from at and was a for a of The of and by for was in and Pdcd1−/− mice at and months as S. Y. T. S. M.R. and for of 2008; PubMed Scopus Google Scholar of was the ocular surface of the The ocular surface was with to 3 and corneal was a a by The of corneal was a of to 3 for of the of the of the on clinical in J. 1995; Google Scholar and Pdcd1−/− mice at and months of induced and mice with for and and glands and in in with and of organs including the lung, liver, kidney, pancreas, and in and and Pdcd1−/− mice. of of dacryoadenitis and was on the of Immunol. Google Scholar as to being of cells 2 such 3 of 4 of the glands and with in to the 4 In glands for The of inflammatory in the lung, liver, pancreas, and was the J. Y. Chen J. I. Wang L. and PD-1 T-cell Natl Acad Sci U S A. PubMed Scopus Google Scholar as of 2 of activated 3 of was to H. M. H. N. Honjo T. 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The of CD4+ T cells and CD19+ B cells and The of inflammatory in in of CD4+ T cells from Pdcd1−/− mice was that in of CD4+ T cells from mice the dacryoadenitis was in of CD19+ B cells from Pdcd1−/− mice. in in of from mice is in The of of CD4+ T cells from Pdcd1−/− mice showed massive the of in mice of CD4+ T cells from Pdcd1−/− mice was to that in cells from mice was in the organs, including the lung, liver, pancreas, and in of CD4+ T cells from Pdcd1−/− mice Flow-cytometric analysis of was to the of infiltrating immune cells into with dacryoadenitis induced by transfer of CD4+ T cells from Pdcd1−/− mice. Among infiltrating cells, CD3+ T cells CD19+ B cells and Among infiltrating CD3+ T cells, CD4+ T cells and T cells The of T cells CD3+ T cells was that of CD4+ T cells weeks the transfer of CD4+ T cells of Pdcd1−/− mice and In mouse PD-1 leads to various of autoimmune on Pdcd1−/− mice with background develop autoimmune H. Okazaki T. Y. K. M. A. S. A. H. N. Honjo T. in PD-1 2001; PubMed Scopus Google Scholar the Pdcd1−/− mice with background develop disorders in multiple organs, including the kidney, liver, and H. M. H. N. Honjo T. Development of autoimmune by of the PD-1 gene an 11: Full Text Full Text PDF PubMed Scopus Google J. Y. Chen J. I. Wang L. and PD-1 T-cell Natl Acad Sci U S A. PubMed Scopus Google Scholar of the and is induced in of the Pdcd1−/− Y. Wood C.R. Chernova T. Chaudhary D. Borde M. Chernova I. Iwai Y. Long A.J. Brown J.A. Nunes R. Greenfield E.A. Bourque K. Boussiotis V.A. Carter L.L. Carreno B.M. Malenkovich N. Nishimura H. Okazaki T. Honjo T. Sharpe A.H. Freeman G.J. PD-L2 is a second ligand for PD-1 and inhibits T cell activation.Nat Immunol. 2001; 2: 261-268Crossref PubMed Scopus Google Scholar Pdcd1−/− mice with background to the absence of the PD-1 pathway affected immune in was for the that at months of age, and at months of age, in Pdcd1−/− mice with in mice. Moreover, the showed that corneal at months of was in Pdcd1−/− mice in mice. However, the at months was and in cell and Pdcd1−/− mice at and months of age. cell as a ocular surface was in Pdcd1−/− mice. mouse the of In Pdcd1−/− mice developed dacryoadenitis and from 3 to 4 months of age. These results indicate that the of of in and is that in organs in Pdcd1−/− mice. dacryoadenitis and in Pdcd1−/− mice, and destruction in in with the results of the of and The and number of of of in mice with age, and are to of syndrome mice, and immune with in mice develop in A.J. E.A. G.J. surface disease and dacryoadenitis in Full Text Full Text PDF PubMed Scopus Google Y. M. M. N. K. of in in production in 11: PubMed Scopus (7) Google Scholar The in in mice in the is with the results of The of infiltrating cells in and as infiltrating cells in Pdcd1−/− mice. indicate that of infiltrating cells to the of the in the early stage of dacryoadenitis. of in autoimmune in and in mouse of syndrome that mouse and I. of on in mouse of PubMed Scopus Google Scholar dacryoadenitis and are in in and mice. In mice, dacryoadenitis is in in In Pdcd1−/− mice, dacryoadenitis and in in at and months of age. These results indicate that the autoimmune leading to of dacryoadenitis and in Pdcd1−/− mice. The showed that in and Pdcd1−/− mice, in Pdcd1−/− mice, and in mice, at months with that at The of in mice with age, and the of in is in in A.J. E.A. G.J. surface disease and dacryoadenitis in Full Text Full Text PDF PubMed Scopus Google Y. M. M. N. K. of in in production in 11: PubMed Scopus (7) Google Scholar The in in mice in the was with that in the the and destruction of in and Pdcd1−/− mice the in in and Pdcd1−/− mice to that the of in is that is an important for in of an in the Full Text Full Text PDF PubMed Scopus Google The of in Full Text Full Text PDF PubMed Scopus Google Scholar and the of by regulation of by lacrimal cells in Immunol. Google J. control of in the lacrimal 1995; PubMed Scopus Google Scholar in Pdcd1−/− mice the of in Pdcd1−/− mice, in of of the of cells in the of syndrome that CD4+ cells a analysis of in syndrome Immunol. Google Scholar and are to lymphocyte in and The with the of the of Exp Immunol. 2002; PubMed Scopus Google M. T. Y. S. A. T. S. to the and of Exp Immunol. 2012; PubMed Scopus Google T. M. A. S. Y. K. S. of T in salivary glands from syndrome Exp Immunol. 2012; PubMed Scopus Google F. J. R. J. D. Th1 and expression in salivary glands from with PubMed Scopus Google Y. S. M. A. T. A. K. K. expression in the salivary glands of with Rheum. 1996; PubMed Scopus Google Scholar in mouse of syndrome reported that dacryoadenitis in mice is a immune M. N. K. N. Saito I. Y. of autoimmune dacryoadenitis in mice on Exp Immunol. PubMed Scopus Google Scholar dacryoadenitis in mice is a immune Lee B. J.A. Th1 immune in autoimmune lacrimal disease in 2000; Google Scholar In the that the cells infiltrating the T cells in the of dacryoadenitis at 3 to 4 months of age, by B cells as the mice Moreover, analysis of production that only associated was by the CD4+ cells infiltrating the that Th1 cells are mainly in the stage of dacryoadenitis in Pdcd1−/− mice. was by the of The of and and in the early stage of dacryoadenitis in Pdcd1−/− mice to in mice, the of and the of in in Pdcd1−/− mice. the results of lymphocyte transfer showed that CD4+ T cells in the of autoimmune dacryoadenitis in Pdcd1−/− mice. These results confirmed that dacryoadenitis in Pdcd1−/− mice was induced by immune response in the early and that and immune in In that of in mice was of CD4+ T cells, T cells, and a CD19+ B cells weeks transfer of CD4+ T cells of mice. CD4+ T cells from mice to B cells, B cells of to by the of such as and results the mechanism of dacryoadenitis that CD4+ T cells immune T cells and B cells, and weeks the transfer of CD4+ T cells in Pdcd1−/− mice, CD3+ T cells infiltrating immune cells in and the of T cells CD3+ T cells was that in CD4+ T cells, In the infiltrating cell of with dacryoadenitis of Pdcd1−/− mice, CD3+ T cells at months CD19+ B cells at months B cells infiltrating cells of weeks transfer of CD4+ T cells in Pdcd1−/− mice. was in of CD4+ T cells from Pdcd1−/− mice at weeks In the mice of induced a in including regulatory T cells, the in regulatory T cells is to to of dacryoadenitis induced by transfer of CD4+ T cells in Pdcd1−/− mice, and the of of in mice. These results indicate that CD4+ Th1 cells a role in the of dacryoadenitis in Pdcd1−/− mice. The of the PD-1 pathway by nivolumab was reported to T-cell a response and response in from with J. G.J. S. L.J. J.A. H. A.M. PD-1 Th1 and and suppresses in from with and 2012; PubMed Scopus Google Scholar Sicca syndrome as an adverse effect of nivolumab caused by immune response in The of in is of the for and has important Nishimura H. M. H. N. Honjo T. Development of autoimmune by of the PD-1 gene an 11: Full Text Full Text PDF PubMed Scopus Google Scholar reported that such as antibody and in Pdcd1−/− mice. the of and autoantibodies in and Pdcd1−/− mice at and to months of age, Pdcd1−/− mice a of of the of of The expression of PD-L1 on nonhematopoietic cells the of T cells into organs and tissue caused by cell I. A. M. Freeman G.J. Sharpe A.H. expression of PD-L1 T cell Exp Med. 2006; PubMed Scopus Google Scholar However, as by of from Pdcd1−/− mice with nonhematopoietic cells including and cells PD-1 the infiltrating expressed PD-L1 and PD-L2 In a of in mice, was that in the absence of corneal corneal J. S. Freeman G.J. Sharpe A.H. R. of T-cell by programmed in corneal PubMed Scopus Google Scholar and the the of the pathway in the of dacryoadenitis and is that dacryoadenitis in Pdcd1−/− mice and corneal in mice are T-cell and expression are that inflammatory a the showed that PD-L1 in to corneal maintain immune Moreover, the showed that dacryoadenitis in Pdcd1−/− mice was caused by Th1 immune response and was associated with cells. corneal is as a immune that of the mechanisms. reported of in and in syndrome I. K. M. S. K. T. K. N. Expression of cell molecules in the salivary and lacrimal glands of PubMed Scopus Google D. J. expression in salivary of Immunol. Google Scholar and H. Saito I. N. Y. N. Y. of of autoimmune in Immunol. PubMed Scopus Google Scholar The of such as and in in Pdcd1−/− mice in mice at months of age. The of with in Pdcd1−/− mice. These results are with from that that such as and in D. D. of in the associated with autoimmune 2002; Google Scholar The in in effect a in production in Pdcd1−/− mice. Moreover, in the Pdcd1−/− mice developed and a of with that the PD-1 pathway maintains immune only in in the salivary In the the role of PD-1 in the regulation of immune in was The results indicate that CD4+ Th1 cells to the of autoimmune and PD-1 expressed on infiltrating cells in in of in Pdcd1−/− mice. These results that the PD-1 pathway the of and that PD-1 plays an important role in the of immune in an for syndrome induced by such as nivolumab. for with the are to for and and the and the and the and the results of the and the and and the of the the of the of CD4+ T cells and CD19+ B cells cell CD4+ T cells CD19+ B cells by with CD4+ CD19+ The cells with and of cell are CD4+ T cells, was with CD19+ B cells, was are of

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