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Intrathymic Proliferation Wave Essential for V 14 Natural Killer T Intrathymic proliferation wave essential for V␣14؉ natural killer T cell development depends on c-Myc Marei Dosea, Barry P. Sleckmanb, Jin Hanc, Andrea L. Bredemeyerb, Albert Bendelacc, and Fotini Gounaria,1 aCommittee on Immunology, Department of Medicine, Rheumatology, and cHoward Hughes Medical Institute, Committee on Immunology, Department of Pathology, University of Chicago, Chicago, IL 60637; and bDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 Edited by Harvey Cantor, Dana–Farber Cancer Institute, Boston, MA, and approved April 2, 2009 (received for review December 2, 2008) The molecular requirements for invariant V␣14-bearing natural the 100-fold more frequent CD44low stage 1 (ST1), they expand killer T cells (iNKT) in the thymus are poorly understood. A minute in numbers and down-regulate CD24. Both ST1 and the subse- Ϫ population of Ϸ500 newly selected CD69؉CD24؉ stage 0 (ST0) iNKT quent CD44high stage 2 (ST2) are NK1.1 . Most recent thymic ϩ cells gives rise to Ϸ100 times more CD44neg/loCD24؊ stage 1 (ST1) emigrants resemble CD4 ST2 cells and up-regulate NK cell cells, which then generate similar frequencies of CD44hiCD24؊ markers only as they mature in the periphery (9, 10), whereas an high ϩ stage 2 (ST2) and mature iNKT cells. Although the increased independent set of long-lived CD44 NK1.1 stage 3 (ST3) cells develop in the thymus (11). Apart from NK1.1, DX5 that number of ST1 compared with ST0 cells indicates the initiation of ␣ a proliferation wave in the very early stages of iNKT cell develop- detects an epitope of 2 integrin (CD49b) can be used in conjunction with CD1d tetramers to identify later stage iNKT ment, details about the controlling mechanism are currently lack- ϩ ϩ cells, although NK1.1 and DX5 populations are not identical ing. Here, we show that the transcription factor c-Myc is required (12, 13). iNKT cell stages display differences in cytokine mRNA for iNKT cell development. Conditional ablation of c-Myc in double- expression and cytokine release on stimulation. Although ST1 positive thymocytes specifically impacted iNKT but not conven- cells produce predominantly IL-4, subsequent stages also acquire tional T cell development. Within the iNKT population, a progres- the capability to produce IFN-␥ as they mature, as deduced from sive reduction of iNKT cells was observed starting at ST1 (Ϸ50-fold) in vitro receptor stimulation experiments and cytokine reporter and ST2 (Ϸ350-fold), with a complete lack of mature cells in knockin mice (1, 14). Two recent reports describe the zinc finger thymus, spleen, and liver. ST0/ST1 c-Myc-deficient iNKT cells transcription factor Plzf as an essential regulator of the iNKT cell IMMUNOLOGY showed reduced proliferation. In contrast, annexin V staining did effector phenotype (15, 16). Several other transcription factors not reveal increased apoptosis, and transgenic overexpression of have been implicated in iNKT cell development and function BCL-2 did not rescue iNKT cell development in c-Myc-deficient mice. (17). However, despite strong evidence indicating that the low Moreover, expression of known iNKT differentiation factors such infrequent CD44 iNKT precursors undergo massive expan- as Plzf and Gata3 was not dramatically altered. These, findings sion as they develop in the thymus, the factors that control cell provide compelling evidence that c-Myc mediates an intrathymic cycling and their overall impact on iNKT cell development remain unknown. proliferation wave immediately after agonist selection of iNKT cells The basic region/helix–loop–helix/leucine zipper (bHLHZip) and illustrate the importance of this expansion for the generation transcription factor myelocytomatosis oncogene (c-Myc) plays of mature iNKT cells in vivo. an integral role in proliferation, survival, and differentiation of normal and neoplastic cells. Myc binds E-box DNA motifs as a iNKT cells ͉ cell cycle ͉ nonconventional lymphocytes heterodimer with Max, resulting in cell cycle entry (18) and transcriptional activation or suppression of genes. c-Myc has atural killer T cells develop in the thymus and are charac- been implicated in cell proliferation (19) as well as the control Nterized by the expression of various surface molecules of cell growth. Its expression increases rapidly in response to originally detected on natural killer (NK) cells (1). The majority growth factors, B cell receptor or TCR ligation, and conventional of murine NKT cells, referred to as iNKT, express a semiinvari- CD4 T cells expressing hypomorphic c-Myc alleles display pro- ant T cell receptor (TCR) repertoire with invariant V␣14-J␣18 found defects in activation induced proliferation (20). We and ␤ ␤ ␤ others have shown that c-Myc is essential for development at the usage in combination with V 8, V 7, or V 2 (2). Most exoge- pre-TCR checkpoint (21, 22). c-Myc has also been reported to nous ligands for NKT cells identified so far are components of control the self-renewal of hematopoietic stem cells (HSCs) (23), the cell wall of Gram-negative bacteria, implying an important and its conditional ablation in the bone marrow favored self- role in innate immunity, but they also display autoreactivity and renewal over differentiation of HSCs in the stem cell niche (24). have been implicated in autoimmune disease and cancer (re- Here, we show that c-Myc is essential for iNKT cell develop- viewed in ref. 1). ment. Conditional ablation of c-Myc at the DP stage in mice iNKT cells are positively selected on CD1d, an MHCI-like leads to a dramatic reduction of iNKT cells. CD44low Myc- molecule expressed on cortical CD4ϩCD8ϩ [double-positive deficient iNKT cells are not prone to apoptosis but proliferate (DP)] thymocytes in an agonist selection process involving less, providing evidence that c-Myc is involved in controlling the endogenous ligands, including the glycosphingolipid isoglobotri- proliferation wave of early iNKT cell development. hexosyl ceramide (iGb3) (3–5). iNKT cell selection is profoundly Results different from positive selection of conventional T cells, and coreceptor interactions are likely involved in the process. As an Myc Deficiency Disproportionately Impairs iNKT Cell Development. We have previously reported a strict requirement for the tran- example, homophilic interactions of SLAM and Ly108 surface scription factor c-Myc in the expansion of thymocytes undergo- molecules between iNKT and DP thymocytes induce activation of the Src kinase FynT leading to expansion and differentiation of immature iNKT cells (1). Author contributions: M.D., A.B., and F.G. designed research; M.D. and J.H. performed The development of CD1d tetramers loaded with ␣-galactosyl research; B.P.S. and A.L.B. contributed new reagents/analytic tools; M.D. analyzed data; ceramide (␣-GalCer) (6, 7) as a tool to label iNKT cells allowed and M.D. and F.G. wrote the paper. the identification of an extremely infrequent (Ϸ1/106) stage 0 The authors declare no conflict of interest. ϩ (ST0) CD24hiCD69 precursor population thought to represent This article is a PNAS Direct Submission. cells immediately after positive selection (8). As cells progress to 1To whom correspondence should be addressed. E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0812255106 PNAS Early Edition ͉ 1of6 Downloaded by guest on September 24, 2021 Fig. 1. Myc deficiency disproportionately impairs iNKT cell development. BALB/c control and CD4Cre Mycfl/fl mice were analyzed at 4–8 weeks of age. (A) (Upper) Representative FACS plots depicting CD4 and CD8 surface expression on lymphocytes from thymus and spleen. (B)(Upper) Invariant iNKT cell populations in thymus, spleen, and liver. (A and B)(Lower) Absolute cell numbers are given as histograms. N ϭ number of experimental mice per genotype indicated here. B, BALB/c; M, CD4Cre Mycfl/fl.(C) Quantitative PCR for Myc mRNA expression was performed on cDNA obtained from the indicated cell populations. No Myc expression was detected in CD4 SP or iNKT ST1 cells from CD4Cre Mycfl/fl mice. (D) iNKT cells from sublethally irradiated bone marrow chimeras were MACS enriched and analyzed by FACS. Host, Thy1.1ϩ BALB/c mice; donor, Thy1.2ϩ CD4Cre Mycfl/fl mice. Analysis was performed 12 weeks after injection. N ϭ 4. ing ␤-selection (21). Here, we show that, although CD4Cre thymus (3.7 Ϯ 0.9 ϫ 105 vs. 9.9 Ϯ 3.2 ϫ 105) and spleen (1.0 Ϯ mediated deletion of c-Myc after ␤-selection has no significant 0.4 ϫ 106 vs. 2.8 Ϯ 0.8 ϫ 106) (Fig. 1B). effect on thymocyte development at large, it specifically prohib- Thus, c-Myc ablation at the DP stage specifically and pro- its the development of iNKT cells (Fig. 1). Cellularity and foundly affected iNKT cells. To examine whether this defect was surface expression of CD4 and CD8 on thymocytes and spleno- cell intrinsic or due to altered properties of c-Myc-deficient DP Ϯ ϫ cells, which are essential for iNKT selection, we also analyzed cytes of BALB/c control and c-Myc-deficient thymi (2.1 0.6 ϩ 108 vs. 1.3 Ϯ 0.4 ϫ 108) and spleens (2.2 Ϯ 0.5 ϫ 108 vs. 2.3 Ϯ sublethally irradiated Thy1.1 BALB/c mice reconstituted with ϩ fl/fl 0.7 ϫ 108) were comparable (Fig. 1A). An up to 50% reduction a 1:1 mixture of host and Thy1.2 CD4Cre Myc donor bone in thymic cellularity with a corresponding reduction in DP cells marrow. These chimeras showed a disproportionate reduction of fl/fl could sometimes be observed but was not statistically significant iNKT cells originating from CD4Cre Myc donors. Thymocyte (1.7 Ϯ 0.5 ϫ 108 vs. 1.0 Ϯ 0.3 ϫ 108). Likewise, CD4Cre Mycfl/fl preparations were enriched for iNKT cells with PBS57 loaded mice tended to have fewer peripheral T cells, but only the CD1d-tetramers (hereafter referred to as tetramer) using mag- netic microbeads.
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