During an immune response, antigen-specific T cells are activated and expand to perform various effector functions that counteract the invading pathogen. there is a massive increase in T cell number during clonal expansion under optimal conditions. When the pathogen has been eliminated, a contraction of T cell number occurs through cell death due to cytokine withdrawal but a small fraction of memory T cells are preserved. The generation of long-lived memory T cells is crucial for generating anamnestic immune responses to a potential re-exposure of pathogens and is the cellular basis of vaccination. On the other hand, programmed cell death is critical to achieve appropriate lymphocyte homeostasis and the prevention of lymphoid malignancy. Homeostasis is also maintained during immune responses. If an activated and cycling T cell is restimulated by its cognate antigen in the presence of interleukin 2 (IL-2) or other gamma chain cytokines, it is driven into an apoptosis death pathway, a process we have called restimulation-induced cell death (RICD). Memory T cells of the CD4 type are segregated into two main subsets: central memory (TCM) and effector memory (TEM) T cells. Our laboratory has shown that TEM cells are more sensitive to RICD than TCM cells and IL-2 is necessary for TEM cell apoptosis. However, the molecular mechanism regulating apoptosis of memory cells remains poorly investigated. The IL-2 signaling pathway transducers signals inside the cell primarily through a transcription factor called signal transducer and activator of transcription 5 (STAT5) which comes in two forms called A and B. We recently identified a patient with a novel heterozygous missense mutation in STAT5B. The clinical phenotype of this patient includes immune thrombocytopenic purpura (ITP), lymphadenopathy, a high level of IgM antibodies but overall hypogammaglobulinemia, and a history of necrotizing granulomas in the lungs. Surprisingly, we found that the patient harbors a higher percentage of TEM cells in the blood compared to healthy subjects. We also found that patients TEM cells are strikingly resistant to RICD in vitro which could explain their accumulation in the blood. These findings are consistent with an excess of TEM cells that has been described in STAT5 deficient mice. Similar to the patients TEM cells, TEM from STAT5b-deficient mice exhibited reduced RICD. In further experiments we carried out with human T cells, we observed that the STAT5 inhibition using a chemical inhibitor caused a complete blockade of TEM RICD. In a transcriptomic analysis of the patients cells, RNA-sequencing revealed a global down-regulation of the IL2 pathway genes in patient T cells compared to healthy subjects. Moreover, in examining the patients mutant we found that the mutant STAT5b was deficient in transcriptional activity using a luciferase reporter assay. Taken together, these data revealed that the homeostasis of memory T cells of the TEM subtype is controlled by IL-2 dependent apoptosis and that a failure of this pathway can lead to an immune to this regulatory disease in humans.
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