STAT5B: A Differential Regulator of the Life and Death of CD4+ Effector Memory T Cells

Abstract

Understanding the control of antigen restimulation-induced T cell death (RICD), especially in cancer immunotherapy where highly proliferating T cells will encounter potentially large amounts of tumor antigens, is important now more than ever. It has been known that growth cytokines make T cells susceptible to RICD, but the precise molecular mediators that govern this in T cell subsets is unknown until now. Signal transducer and activator transcription (STAT) proteins are a family of transcription factors that regulate gene expression programs underlying key immunological processes. In particular, STAT5 is known to favor the generation and survival of memory T cells. Here we report an unexpected role for STAT5 signaling in the death of effector memory T (TEM) cells in mice and humans. TEM cell death was prevented with neutralizing anti-IL-2 antibody or STAT5/JAK3 inhibitors, indicating that STAT5 signaling drives RICD in TEM cells. Moreover, we identified a unique patient with a heterozygous missense mutation in the coiled-coil (CC) domain of STAT5B that presented with autoimmune lymphoproliferative syndrome (ALPS)-like features. Similar to Stat5b−/− mice, this patient exhibited increased CD4+ TEM cells in the peripheral blood. The mutant STAT5B protein dominantly interfered with STAT5-driven transcriptional activity, leading to global downregulation of STAT5-regulated genes in patient T cells upon IL-2 stimulation. Notably, CD4+ TEM cells from the patient were strikingly resistant to cell death by in vitro TCR restimulation, a finding that was recapitulated in Stat5b−/− mice. Hence, STAT5B is a crucial regulator of RICD in memory T cells in mice and humans.

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

“…As expected, LOF STAT5B mutations cause immunodeficiency . Given its critical role in T cell memory, mutations in the STAT5B gene are associated with recurrent pneumonia and other infections . Because of the role of STAT5B in Treg development, deficiency of STAT5B can lead to the combination of lymphopenia and autoimmune disease, manifested by early‐onset juvenile idiopathic arthritis, severe eczema, and immune thrombocytopenic purpura …”

“…11 Given its critical role in T cell memory, mutations in the STAT5B gene are associated with recurrent pneumonia and other infections. 1,34,35 Because of the role of STAT5B in Treg development, deficiency of STAT5B can lead to the combination of lymphopenia and autoimmune disease, manifested by early-onset juvenile idiopathic arthritis, severe eczema, and immune thrombocytopenic purpura. 19,36,37 In addition to the variety of pathologies caused by mutations in 39,40 Similarly, polymorphisms in STAT3, STAT4, and STAT6 loci are associated with a variety of immune diseases.…”

Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond

“…RICD could be a viable approach for this setting. Adding a drug along with gluten provocation that would promote RICD like a STAT5B agonist [32] (Figure 1F) or would interfere with activated T cells' energy metabolism like Teriflunimide [30] could conceivably both lead to a selective elimination of gluten-specific CD4 + T cell clones ( Figure 1G).…”

Involvement of STAT5 in Oncogenesis

“…In addition, STAT5 functions to modulate Forkhead box protein P3 (FoxP3) for the generation of regulatory T cells [ 43 ]. STAT5b is also involved in the antigen re-stimulation T cell death (RICD) of effector memory T cells, which helps to maintain T cell homeostasis in the body [ 44 ]. Typically, STAT5 and STAT3 regulate different genes in cells where they both might be activated, but in some cases, they could also regulate the expression of the same gene [ 34 ].…”