Control of CD8 T cell proliferation and terminal differentiation by active STAT5 and CDKN2A/CDKN2B.

Magali Grange 1 Marilyn Giordano 2 Amandine Mas 3 Romain Roncagalli 1 Guylène Firaguay 2 Jacques Nunes 2 Jacques Ghysdael 4 Anne-Marie Schmitt-Verhulst 1 Nathalie Auphan-Anezin 1
1 CIML - Centre d'Immunologie de Marseille - Luminy
2 CRCM - Centre de Recherche en Cancérologie de Marseille
3 ICGM ICMMM - Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier
4 Service d'hématologie-immunologie-oncologie pédiatrique
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) .
Keywords : effector CD8 T cell gene regulation immunotherapy senescence transcription factor
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Immunology, Wiley, 2015, 145 (4), pp.543-57. 〈10.1111/imm.12471〉
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http://www.hal.inserm.fr/inserm-01420012
Contributeur : Jacques Nunès <>
Soumis le : mardi 20 décembre 2016 - 11:50:40
Dernière modification le : vendredi 31 août 2018 - 08:46:02

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UPMC | ICG | UNIV-AMU | INC-CNRS | CHIMIE | UNIV-MONTPELLIER

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Magali Grange, Marilyn Giordano, Amandine Mas, Romain Roncagalli, Guylène Firaguay, et al.. Control of CD8 T cell proliferation and terminal differentiation by active STAT5 and CDKN2A/CDKN2B.. Immunology, Wiley, 2015, 145 (4), pp.543-57. 〈10.1111/imm.12471〉. 〈inserm-01420012〉

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