Absence of Programmed Death Receptor 1 Alters Thymic Development and Enhances Generation of CD4/CD8 Double-Negative TCR-Transgenic T Cells

Christian Blank, Ian Elliott Brown, Reinhard Marks, Hiroyuki Nishimura, Tasuku Honjo, Thomas F. Gajewski

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79 Scopus citations


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, ∼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 γδ TCR; and the majority did not up-regulate CD8αα expression upon activation, arguing that they are not predominantly diverted γδ-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 αβ peripheral T cells.

Original languageEnglish (US)
Pages (from-to)4574-4581
Number of pages8
JournalJournal of Immunology
Issue number9
StatePublished - Oct 1 2003
Externally publishedYes


ASJC Scopus subject areas

  • Immunology

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