Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals
| Autor: | Samarchith P. Kurup, John T. Harty, Gabriel R. Starbeck-Miller, Marie T. Kim |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Interleukin 2 CD86 Effector Immunology hemic and immune systems chemical and pharmacologic phenomena Dendritic cell Biology Cell biology 03 medical and health sciences 030104 developmental biology medicine.anatomical_structure medicine Immunology and Allergy Cytotoxic T cell Signal transduction Memory T cell CD80 medicine.drug |
| Zdroj: | The Journal of Immunology. 197:1754-1761 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | As a result of the growing burden of tumors and chronic infections, manipulating CD8 T cell responses for clinical use has become an important goal for immunologists. In this article, we show that dendritic cell (DC) immunization coupled with relatively early (days 1–3) or late (days 4–6) administration of enhanced IL-2 signals increase peak effector CD8 T cell numbers, but only early IL-2 signals enhance memory numbers. IL-2 signals delivered at relatively late time points drive terminal differentiation and marked Bim-mediated contraction and do not increase memory T cell numbers. In contrast, early IL-2 signals induce effector cell metabolic profiles that are more conducive to memory formation. Of note, downregulation of CD80 and CD86 was observed on DCs in vivo following early IL-2 treatment. Mechanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevented the decrease in CD80 and CD86, supporting a cell-extrinsic role for CTLA-4 in downregulating B7 ligand expression on DCs. Finally, DC immunization followed by early IL-2 treatment and anti–CTLA-4 blockade resulted in lower memory CD8 T cell numbers compared with the DC+early IL-2 treatment group. These data suggest that curtailed signaling through the B7-CD28 costimulatory axis during CD8 T cell activation limits terminal differentiation and preserves memory CD8 T cell formation; thus, it should be considered in future T cell–vaccination strategies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|