Control of CD8 T cell proliferation and terminal differentiation by active STAT5 and CDKN2A/CDKN2B.
Immunology
; 145(4): 543-57, 2015 Aug.
Article
en En
| MEDLINE
| ID: mdl-25882552
ABSTRACT
CD8 T cells used in adoptive immunotherapy may be manipulated to optimize their effector functions, tissue-migratory properties and long-term replicative potential. We reported that antigen-stimulated CD8 T cells transduced to express an active form of the transcription factor signal transducer and activator of transcription 5 (STAT5CA) maintained these properties upon adoptive transfer. We now report on the requirements of STAT5CA-expressing CD8 T cells for cell survival and proliferation in vivo. We show that STAT5CA expression allows for greater expansion of T cells in vivo, while preserving dependency on T-cell-receptor-mediated tonic stimulation for their in vivo maintenance and return to a quiescent stage. STAT5CA expression promotes the formation of a large pool of effector memory T cells that respond upon re-exposure to antigen and present an increased sensitivity to γc receptor cytokine engagement for STAT5 phosphorylation. In addition, STAT5CA expression prolongs the survival of what would otherwise be short-lived terminally differentiated KLRG1-positive effector cells with up-regulated expression of the senescence-associated p16(INK) (4A) transcripts. However, development of a KLRG1-positive CD8 T cell population was independent of either p16(INK) (4A) or p19(ARF) expression (as shown using T cells from CDKN2A(-/-) mice) but was associated with expression of transcripts encoding p15(INK) (4B) , another protein involved in senescence induction. We conclude that T-cell-receptor- and cytokine-dependent regulation of effector T cell homeostasis, as well as mechanisms leading to senescent features of a population of CD8 T cells are maintained in STAT5CA-expressing CD8 T cells, even for cells that are genetically deficient in expression of the tumour suppressors p16(INK) (4A) and p19(ARF) .
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Diferenciación Celular
/
Linfocitos T CD8-positivos
/
Inhibidor p16 de la Quinasa Dependiente de Ciclina
/
Proliferación Celular
/
Factor de Transcripción STAT5
/
Inhibidor p15 de las Quinasas Dependientes de la Ciclina
Límite:
Animals
Idioma:
En
Revista:
Immunology
Año:
2015
Tipo del documento:
Article
País de afiliación:
Francia