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Gfi1-Foxo1 Axis Controls the Fidelity of Effector Gene Expression And

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Gfi1-Foxo1 Axis Controls the Fidelity of Effector Gene Expression And Gfi1-Foxo1 axis controls the fidelity of effector gene PNAS PLUS expression and developmental maturation of thymocytes Lewis Zhichang Shia,1,2, Jordy Saraviaa,1, Hu Zenga, Nishan S. Kalupahanaa,3, Clifford S. Guya, Geoffrey Nealeb, and Hongbo Chia,4 aDepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and bHartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital, Memphis, TN 38105 Edited by Stephen M. Hedrick, University of California, San Diego, La Jolla, CA, and accepted by Editorial Board Member Arthur Weiss November 28, 2016 (received for review October 26, 2016) Double-positive (DP) thymocytes respond to intrathymic T-cell re- immature thymocytes while repressing the expression of effector ceptor (TCR) signals by undergoing positive selection and lineage molecules unique to mature T cells (4). However, given the multi- differentiation into single-positive (SP) mature cells. Concomitant faceted functions of E-proteins in thymocyte selection and survival with these well-characterized events is the acquisition of a mature T- (5), how E-proteins propagate signals in DP cells is unclear (1). cell gene expression program characterized by the induction of the Therefore, despite our increasing knowledge of the cellular events in α effector molecules IL-7R , S1P1, and CCR7, but the underlying mech- thymocyte selection and lineage differentiation, the underlying anism remains elusive. We report here that transcription repressor mechanisms and transcriptional circuitry for the maturation of DP Growth factor independent 1 (Gfi1) orchestrates the fidelity of the thymocytes remain to be determined. DP gene expression program and developmental maturation into SP Growth factor independent 1 (Gfi1), a transcriptional repressor, cells. Loss of Gfi1 resulted in premature induction of effector genes has emerged as an important regulator of hematopoietic and im- and the transcription factors forkhead box protein O1 (Foxo1) and Klf2 in DP thymocytes and the accumulation of postselection inter- mune system cells. Gfi1 is required for the normal development and mediate populations and accelerated transition into SP cells. Strik- homeostasis of hematopoietic stem cells and both myeloid and ingly, partial loss of Foxo1 function, but not restored survival fitness, lymphoid progenitors (6). Specifically, loss of Gfi1 impairs the de- rectified the dysregulated gene expression and thymocyte matura- velopment of neutrophils and B cells while expanding the monocyte tion in Gfi1-deficient mice. Our results establish the Gfi1-Foxo1 axis and myeloid populations (7). During T-cell development, Gfi1 ex- and the transcriptional circuitry that actively maintain DP identity pression is dynamically regulated (8), and its germ-line deficiency and shape the proper generation of mature T cells. impairs DN cell generation (9). Recently, we have established a role Gfi1 | thymocyte maturation | transcription repressor | Foxo1 | apoptosis Significance INFLAMMATION IMMUNOLOGY AND ormal development of T cells in the thymus is essential for the A fundamental question in immunology is the mechanism of Ngeneration of a functional peripheral T-cell pool that mediates thymocyte development, but how differentiating CD4+CD8+ + + efficient immune responses against infections and tumors while double-positive thymocytes progress into CD4 or CD8 single- avoiding uncontrolled self-reactive responses. Generation of T cells positive cells remains poorly defined. We have now determined starts from the thymic settling of early thymic progenitors (ETPs), that the transcription repressor Growth factor independent 1 − − which progress from the CD4 CD8 double-negative (DN) stage (Gfi1) plays a central role in controlling double-positive cell fate + + + through the CD4 CD8 double-positive (DP) stage to mature CD4 and thymocyte maturation. Deletion of Gfi1 in double-positive + or CD8 single-positive (SP, namely CD4SP and CD8SP) thymo- thymocytes induces premature induction of single-positive– cytes. Whereas the majority of thymocytes are eliminated due to specific effector genes and transcription factors Foxo1 and Klf2 either lack of T-cell receptor (TCR) signals (death by neglect) or and accelerated transition into single-positive cells. These de- high-affinity interaction with self-peptide MHC ligands (negative fects are largely rectified upon partial loss of Foxo1 functions, selection), DP cells with low affinity are rescued from death and indicating the critical contribution of aberrant Foxo1 induction to undergo positive selection and develop into SP cells. Recent studies disrupted thymocyte maturation. Our study establishes a mo- have identified a number of transcriptional regulators, such as RAR- lecular mechanism that actively maintains double-positive cell relatedorphanreceptorgamma(t)(RORγt), runt-related tran- identity and shapes the proper generation of mature T cells. scription factor 3 (Runx3), and Th-inducing POZ-kruppel factor (ThPOK), that control positive selection and lineage decision be- Author contributions: L.Z.S., J.S., H.Z., and H.C. designed research; L.Z.S., J.S., H.Z., N.S.K., tween CD4SP and CD8SP T cells (1–3). and C.S.G. performed research; L.Z.S., J.S., H.Z., N.S.K., C.S.G., G.N., and H.C. analyzed In contrast, we have a very limited understanding of the mecha- data; and L.Z.S., J.S., and H.C. wrote the paper. nisms underlying the progression of DP into SP cells, a related but The authors declare no conflict of interest. rather distinct process from positive selection and CD4/CD8 lineage This article is a PNAS Direct Submission. S.M.H. is a Guest Editor invited by the Editorial Board. differentiation (1). Such developmental maturation is characterized by the acquisition of a mature T-cell gene expression program, Data deposition: The data reported in this paper have been deposited in the Gene Ex- α pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE89898). notably the induction of effector molecules IL-7 receptor chain (IL- 1 L.Z.S. and J.S. contributed equally to this work. 7Rα), C-C motif chemokine receptor 7 (CCR7), and sphingosine 2Present address: Department of Genitourinary Medical Oncology, MD Anderson Cancer 1-phosphate receptor 1 (S1P1) in SP cells that are essential for their Center, Houston, TX 77030. proper survival and trafficking (1). Among the few pathways identi- 3Present address: Department of Physiology, Faculty of Medicine, University of Peradeniya, fied to function in DP-to-SP transition, E-proteins play a pivotal role Sri Lanka. by serving as upstream “sensor” transcription factors in differentiating 4To whom correspondence should be addressed. Email: [email protected]. DP thymocytes (1). E-protein activity in DP thymocytes promotes This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. TCRα gene rearrangement and expression of genes characteristic of 1073/pnas.1617669114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1617669114 PNAS | Published online December 19, 2016 | E67–E74 Downloaded by guest on September 29, 2021 CD4 of Gfi1 in the differentiation of thymus-derived T cells (Treg) via (Gfi1 ) that resulted in effective deletion of Gfi1 starting at shaping the production of IL-2 in the thymic microenvironment (10, the DP stage (10). Loss of Gfi1 resulted in profound up-regulation 11). These results indicate a cell context-dependent function for of mature T-cell genes including Foxo1, Klf2, S1pr1, Ccr7, and Gfi1 in the immune system. Il7r in DP cells. In contrast, Gfi1 deletion did not affect ex- To ascertain the functions of Gfi1 in thymocyte maturation, we pression of DP-specific immature genes including Cxcr4 and developed several complementary genetic systems to modulate Gfi1 Rorc (Fig. 1C), nor did it affect DN-to-DP transition as evi- functions. We determined that Gfi1 orchestrates a unique gene denced by comparable percentages of DN and immature single- expression program. Loss of Gfi1 in DP thymocytes resulted in positive cells (Fig. S1D). Notably, the elevated expression of aberrant up-regulation of multiple SP-specific genes in a cell-in- mature T-cell genes in Gfi1CD4 mice was not due to an expanded + + trinsic manner; these include effector molecules for T-cell survival CD69 TCR subset within DP cells because the up-regulation of − − and trafficking such as IL-7Rα, CCR7, and S1P1 and the associated Foxo1, Klf2, S1pr1, Ccr7,andIl7r was evident even in CD69 TCR transcription factors forkhead box protein O1 (Foxo1) and Kruppel- preselection DP cells lacking Gfi1 (Fig. 1D). In addition, the absence like factor 2 (Klf2). Under physiological conditions of DP-to-SP of Gfi1 in DP cells led to increases in both total cellular and nuclear transition, Gfi1 expression was gradually down-regulated, thus Foxo1 protein levels (Fig. 1E), indicating an increased expression of allowing expression of mature T-cell genes when preselection DP both Foxo1 mRNA and protein. Therefore, Gfi1 specifically re- cells progress to postselection DP and SP stages. Therefore, Gfi1 presses induction of mature T-cell genes in DP thymocytes without enforces the identity of DP thymocytes by preventing the premature impacting expression of DP-specific immature genes. expression of SP genes. Mechanistically, this process is contingent upon the ability of Gfi1 to actively suppress Foxo1 expression in DP Gfi1 Intrinsically Represses a Mature Gene Expression Program in DP thymocytes, as heterozygous loss of Foxo1 rescued defective
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