Absence of programmed death receptor 1 alters thymic development and enhances generation of CD4/CD8 double-negative TCR-transgenic T cells.
Programmed death receptor 1 (PD-1) is expressed on thymocytes in addition to activated lymphocyte cells. Its ligation is thought to negatively regulate T cell activation, and PD-1(-/-) mice develop autoimmunity. To study the role of PD-1 on the development and function of a monoclonal CD8(+) T cell population, 2C TCR-transgenic/recombination-activating gene 2(-/-)/PD-1(-/-) mice were generated. Unexpectedly, approximately 30% of peripheral T cells in these mice were CD4/CD8 double negative (DN). Although the DN cells were not activated by Ag-expressing APCs, they functioned normally in response to anti-CD3/anti-CD28. These cells had a naive surface phenotype and lacked expression of NK1.1, B220, and gammadelta TCR; and the majority did not up-regulate CD8alphaalpha expression upon activation, arguing that they are not predominantly diverted gammadelta-lineage cells. The thymus was studied in detail to infer the mechanism of generation of DN peripheral T cells. Total thymus cellularity was reduced in 2C TCR-transgenic/recombination-activating gene 2(-/-)/PD-1(-/-) mice, and a relative increase in DN cells and decrease in double-positive (DP) cells were observed. Increased annexin V(+) cells among the DP population argued for augmented negative selection in PD-1(-/-) mice. In addition, an increased fraction of the DN thymocytes was HSA negative, suggesting that they had undergone positive selection. This possibility was supported by decreased emergence of DN PD-1(-/-) 2C cells in H-2(k) bone marrow chimera recipients. Our results are consistent with a model in which absence of PD-1 leads to greater negative selection of strongly interacting DP cells as well as increased emergence of DN alphabeta peripheral T cells.
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Christian
C
Blank
Ian
I
Brown
Reinhard
R
Marks
Hiroyuki
H
Nishimura
Tasuku
T
Honjo
Thomas F
TF
Gajewski
D000818:Animals; D000941:Antigens / Q000494:pharmacology; D000954:Antigens, Surface / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000096:biosynthesis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D007106:Immune Sera / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D000941:Antigens; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018106:CD28 Antigens; D017252:CD3 Complex; D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D007106:Immune Sera; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C499308:Rag2 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; C064655:V(D)J recombination activating protein 2