Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 4574-4581 |
| Number of pages | 8 |
| Journal | Journal of Immunology |
| Volume | 171 |
| Issue number | 9 |
| State | Published - Oct 1 2003 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
Cite this
Absence of Programmed Death Receptor 1 Alters Thymic Development and Enhances Generation of CD4/CD8 Double-Negative TCR-Transgenic T Cells. / Blank, Christian; Brown, Ian Elliott; Marks, Reinhard; Nishimura, Hiroyuki; Honjo, Tasuku; Gajewski, Thomas F.
In: Journal of Immunology, Vol. 171, No. 9, 01.10.2003, p. 4574-4581.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Absence of Programmed Death Receptor 1 Alters Thymic Development and Enhances Generation of CD4/CD8 Double-Negative TCR-Transgenic T Cells
AU - Blank, Christian
AU - Brown, Ian Elliott
AU - Marks, Reinhard
AU - Nishimura, Hiroyuki
AU - Honjo, Tasuku
AU - Gajewski, Thomas F.
PY - 2003/10/1
Y1 - 2003/10/1
N2 - 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.
AB - 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.
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M3 - Article
VL - 171
SP - 4574
EP - 4581
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 9
ER -