KLF13 sustains thymic memory-like CD8 T cells in BALB/c mice by regulating IL-4–generating invariant natural killer T cells

Laboratory of Cellular and Molecular Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 05/2011; 208(5):1093-103. DOI: 10.1084/jem.20101527
Source: PubMed


"Memory-like T cells" are a subset of thymic cells that acquire effector function through the maturation process rather than interaction with specific antigen. Disruption of genes encoding T cell signaling proteins or transcription factors have provided insights into the differentiation of such cells. In this study, we show that in BALB/c, but not C57BL/6, mice, a large portion of thymic CD4(-)CD8(+) T cells exhibit a memory-like phenotype. In BALB/c mice, IL-4 secreted by invariant natural killer T (iNKT) cells is both essential and sufficient for the generation of memory-like T cells. In C57BL/6 mice, iNKT cells are less abundant, producing IL-4 that is insufficient to induce thymic memory-like CD8(+) T cells. BALB/c mice deficient in the transcription factor Kruppel-like factor (KLF) 13 have comparable numbers of iNKT cells to C57BL/6 mice and extremely low levels of thymic memory-like CD8(+) T cells. This work documents the impact of a small number of KLF13-dependent iNKT cells on the generation of memory-like CD8(+) T cells.

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Available from: Alan M Krensky
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    • "This in vitro generation of innate memory-like CD8 + cells also supports our earlier results that unlike naïve conventional CD8 + T cells, culture-differentiated CD8 + T cells of C3H/HeJ mice express CD44, CD122, Eomes and PLZF along with TLR2 [14]. Although there is a difference in number of thymic CD4 -CD8 + T cells exhibiting memory-like phenotype in BALB/c and C57BL/6 mice [9] [20], we observed little difference in percentage that differentiated from CD4 "
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    ABSTRACT: Nonconventional innate memory CD8(+) T cells characteristically expressing CD44, CD122, eomesodermin (Eomes) and promyelocytic leukemia zinc finger (PLZF) were derived in culture from CD4(+)CD8(+) double positive (DP) thymocytes of normal BALB/c and C57BL/6 mice. These culture-differentiated cells constitutively express toll-like receptor (TLR)4 and release interferon (IFN)-γ and interleukin (IL)-10. We show the TLR4-ligand lipopolysaccharide (LPS) stimulate the TLR and up-regulate IFN-γ skewing the cells towards type 1 polarization. In presence of LPS these cells also express suppressor of cytokine signaling (SOCS)1 and thus suppress IL-10 expression. In contrast, heat shock protein (Hsp)70 down-regulated TLR4 augmenting the anti-inflammatory cytokine IL-10. In association with IL-10 release IFN-γ was abrogated. The programmed cell death (PD)-1 mostly present in regulatory T cells was stimulated in these IL-10 producing cells by Hsp70 and not LPS indicating the cells can be driven to two contrast outcomes by the two TLR4 ligands. Our work provides a scope for in vitro monitoring of CD8(+) T cells to decipher important immune therapeutic option during infection or sepsis. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Feb 2015 · Cytokine
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    • "IL-4 is required for in vivo CD8+ ILL development [11], [13]–[15], [25], [30] and in vitro treatment of WT thymocytes with IL-4 was sufficient to induce Eomes protein expression in CD8SP thymocytes (Figure 1A) and mRNA (Figure 2B, 3B). Specificity of Eomes staining was confirmed with an isotype control antibody (Figure S1). "
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    ABSTRACT: Interleukin (IL)-4 is a cytokine classically associated with CD4+ T helper type 2 differentiation, but has been recently shown to also be required for the development of CD8+ innate-like lymphocytes. CD8+ innate-like lymphocytes are non-conventional lymphocytes that exhibit characteristics typically associated with memory CD8+ T cells, including expression of the T-box transcription factor Eomesodermin (Eomes). Here we investigate the signaling pathways required for IL-4 induction of Eomes and CD8+ innate-like lymphocyte markers in murine CD8SP thymocytes and peripheral CD8+ T cells. We demonstrate that IL-4 is sufficient to drive Eomes expression and the CD8+ innate-like lymphocyte phenotype through cooperation between STAT6- and Akt-dependent pathways. Furthermore, we show that while IL-4 has little effect on the induction of Eomes in the setting of robust T cell receptor (TCR) activation, this cytokine promotes Eomes in the setting of attenuated TCR stimulation in mature CD8+ T cells suggesting that cytokine signaling pathways may direct cell fate when TCR signals are limiting.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Previous research demonstrates that Balb/c mice express a population of thymic NKT cells that are greater in number and express higher levels of IL-4 compared to C57Bl/6 mice [51]. This may be particularly important in models of obesity, as IL-4 has been linked to protection from metabolic dysregulation. "
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    ABSTRACT: Current estimates suggest that over one-third of the adult population has metabolic syndrome and three-fourths of the obese population has non-alcoholic fatty liver disease (NAFLD). Inflammation in metabolic tissues has emerged as a universal feature of obesity and its co-morbidities, including NAFLD. Natural Killer T (NKT) cells are a subset of innate immune cells that abundantly reside within the liver and are readily activated by lipid antigens. There is general consensus that NKT cells are pivotal regulators of inflammation; however, disagreement exists as to whether NKT cells exert pathogenic or suppressive functions in obesity. Here we demonstrate that CD1d(-/-) mice, which lack NKT cells, were more susceptible to weight gain and fatty liver following high fat diet (HFD) feeding. Compared with their WT counterparts, CD1d(-/-) mice displayed increased adiposity and greater induction of inflammatory genes in the liver suggestive of the precursors of NAFLD. Calorimetry studies revealed a significant increase in food intake and trends toward decreased metabolic rate and activity in CD1d(-/-) mice compared with WT mice. Based on these findings, our results suggest that NKT cells play a regulatory role that helps to prevent diet-induced obesity and metabolic dysfunction and may play an important role in mechanisms governing cross-talk between metabolism and the immune system to regulate energy balance and liver health.
    Full-text · Article · Jan 2014 · PLoS ONE
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