Control of CD 8 T cell proliferation and terminal differentiation by active STAT 5 and CDKN 2A/ CDKN 2B

Summary CD 8 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 CD 8 T cells transduced to express an active form of the transcription factor signal transducer and activator of transcription 5 ( STAT 5 CA ) maintained these properties upon adoptive transfer. We now report on the requirements of STAT 5 CA ‐expressing CD 8 T cells for cell survival and proliferation in vivo . We show that STAT 5 CA 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. STAT 5 CA 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 STAT 5 phosphorylation. In addition, STAT 5 CA expression prolongs the survival of what would otherwise be short‐lived terminally differentiated KLRG 1‐positive effector cells with up‐regulated expression of the senescence‐associated p16 INK 4A transcripts. However, development of a KLRG 1‐positive CD 8 T cell population was independent of either p16 INK 4A or p19 ARF expression (as shown using T cells from CDKN 2A −/− 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 CD 8 T cells are maintained in STAT 5 CA ‐expressing CD 8 T cells, even for cells that are genetically deficient in expression of the tumour suppressors p16 INK 4A and p19 ARF .