Aberrant gene expression by CD25+CD4+ immunoregulatory T cells in autoimmune-prone rats carrying the human T cell leukemia virus type-I gene.
Transgenic rats expressing the env-pX gene of human T cell leukemia virus type-I under the control of the viral long terminal repeat promoter (env-pX rats) developed systemic autoimmune diseases. Prior to disease manifestation, the immunosuppressive function of CD25(+)CD4(+) T (T-reg) cells was impaired in these rats. Since T cell differentiation appeared to be disordered in env-pX rats, we assumed that the impairment of T-reg cells might be caused by an abortive differentiation in the thymus. However, reciprocal bone marrow transfers between env-pX and wild-type rats revealed that direct effects of the transgene unrelated to the thymus framework induced the abnormality of T-reg cells. To identify molecular changes, comparative analyses were done between env-pX and wild-type T-reg cells. Expression of the Foxp3 gene and cell-surface markers supported a naive phenotype for env-pX T-reg cells. Array analyses of gene expression showed some interesting profiles, e.g. up-regulation of genes associated with the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways in env-pX T-reg cells. Additionally, expression of the suppressor of cytokine signaling (SOCS) family genes, which inhibit the JAK/STAT signals, was extremely low in env-pX T-reg cells. These findings suggest that the transgene may mediate the down-regulation of the SOCS family genes and that subsequent excess signals through the JAK/STAT pathways may result in the loss of function of env-pX T-reg cells. We suggest that investigation of the pathology of T-reg cells in our autoimmune-prone rat model may aid in understanding the roles of T-reg cells in human autoimmune diseases.
Hayase
Hiroko
H
Department of Pathology/Pathophysiology, Division of Pathophysiological Science, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Ishizu
Akihiro
A
Ikeda
Hitoshi
H
Miyatake
Yukiko
Y
Baba
Tomohisa
T
Higuchi
Masato
M
Abe
Asami
A
Tomaru
Utano
U
Yoshiki
Takashi
T
D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000032:analysis; D001327:Autoimmune Diseases / Q000276:immunology*; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000235:genetics; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology*; D017874:Immediate-Early Proteins / Q000276:immunology / Q000378:metabolism; D053613:Janus Kinase 1; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology; D051381:Rats; D015375:Receptors, Interleukin-2 / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology
D015703:Antigens, CD; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D053613:Janus Kinase 1; D011505:Protein-Tyrosine Kinases; D015375:Receptors, Interleukin-2; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C500522:Foxp3 protein, rat; C491589:Socs1 protein, rat; C491408:Socs2 protein, rat; C491410:Socs3 protein, rat; C507904:JAK1 protein, human; C507906:Jak1 protein, rat