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

Summary 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 p16INK4A transcripts. However, development of a KLRG1‐positive CD8 T cell population was independent of either p16INK4A or p19ARF expression (as shown using T cells from CDKN2A−/− mice) but was associated with expression of transcripts encoding p15INK4B, 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 p16INK4A and p19ARF.