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1.  Girl Power: Estrogen promotes HSC self-renewal 
Cell stem cell  2014;14(2):137-138.
Although some hematopoietic cell types are known to respond to sex hormones, hematopoietic stem cells (HSCs) are generally thought to function similarly in both sexes. Recently in Nature, Nakada et al. (2014) show that HSCs respond to higher levels of estrogen in females resulting in enhanced self-renewal and increased erythropoiesis.
PMCID: PMC3974548  PMID: 24506879
2.  Increased level of E protein activity during iNKT development promotes differentiation of iNKT2 and iNKT17 subsets 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(10):10.4049/jimmunol.1301546.
E protein transcription factors, and their natural inhibitors, Id proteins, play critical and complex roles during lymphoid development. Here we report that partial maintenance of E protein activity during positive selection results in a change in the cell fate determination of developing iNKT cells, with a block in the development of iNKT1 cells, and a parallel increase in the iNKT2 and iNKT17 subsets. Since the expression levels of the transcription factors that drive these alternative functional fates (GATA-3, RORγT, T-bet and Runx-3) are not altered, our results suggest that E protein activity controls a novel checkpoint that regulates the number of iNKT precursors that choose each fate.
PMCID: PMC3832958  PMID: 24123679
E protein; Id; iNKT; T-bet; Runx-3; GATA-3; RORγT
3.  Interferon regulatory factor 4 promotes cutaneous dendritic cell migration to lymph nodes during homeostasis and inflammation1 
Migration of resident dendritic cells (DC) from the skin to local lymph nodes (LN) triggers T cell-mediated immune responses during cutaneous infection, autoimmune disease and vaccination. Here we investigated whether the development and migration of skin resident DC were regulated by interferon regulatory factor 4 (IRF4), a transcription factor that is required for the development of CD11b+ splenic DC. We found that the skin of naïve IRF4−/− mice contained normal numbers of epidermal Langerhans cells (eLC) and increased numbers of CD11b+ and CD103+ dermal DC populations, indicating that tissue DC development and skin residency is not disrupted by IRF4 deficiency. In contrast, numbers of migratory eLC and CD11b+ dermal DC were significantly reduced in the cutaneous LN of IRF4−/− mice, suggesting a defect in constitutive migration from the dermis during homeostasis. Upon induction of skin inflammation, CD11b+ dermal DC in IRF4−/− mice did not express the chemokine receptor CCR7, and failed to migrate to cutaneous LN, while the migration of eLC was only mildly impaired. Thus, while dispensable for their development, IRF4 is crucial for the CCR7-mediated migration of CD11b+ dermal DC, a predominant population in murine and human skin that plays a vital role in normal and pathogenic cutaneous immunity.
PMCID: PMC3448873  PMID: 22933627
4.  Estrogen receptors regulate an inflammatory pathway of dendritic cell differentiation: mechanisms and implications for immunity 
Hormones and behavior  2012;62(3):254-262.
Immune cells and hematopoietic progenitors express estrogen receptors (ER). As ligand-activated transcription factors that modulate chromatin structure, ER regulate transcriptional programs that direct the development or functional responses of immune cells. ER-regulated immune responses likely contribute to significant sex biases in infection, autoimmunity and other inflammatory diseases, and changes in immune function during the female hormonal cycle and pregnancy. Here we summarize our own and others’ studies showing that ERα signaling regulates the development of dendritic cells (DCs), antigen-presenting cells crucial for initiation of innate and adaptive immunity. During inflammation, elevated GM-CSF directs the development of new DCs from monocytes or other precursors that infiltrate tissues and lymphoid organs, and these de novo populations of inflammatory DCs have critical roles in programming T cell-mediated responses during infection and autoimmunity. Estradiol acting via ERα, but not ERβ, promotes the GM-CSF-mediated inflammatory pathway of DC differentiation, leading to the development of DCs with increased functional capacity. Estradiol/ERα signaling acts directly in GM-CSF-stimulated myeloid progenitors to induce elevated levels of IRF4, a transcription factor that directs a developmental program underlying CD11b+ DC differentiation. In contrast, during homeostatic Flt3 Ligand-driven DC development, ERα signaling decreases numbers of myeloid progenitors and differentiated DCs, yet promotes more functionally competent DCs. Thus ERα signaling regulates the response of DC progenitors to the external cytokine environment, thereby altering the strength or integrity of DC developmental pathways. The development of increased numbers of DCs during inflammation will likely increase the magnitude of DC-mediated functional responses including cytokine production, processing and MHC-mediated presentation of antigens, and activation and polarization of T and B lymphocytes; these functions also may be regulated directly by ERα signaling. In sum, via profound effects on DC development and ensuing functional responses, ERα signaling can regulate the quality of the adaptive immune responses and influence the resolution of infection or chronic inflammatory diseases.
PMCID: PMC3415586  PMID: 22561458
Estrogen; Estrogen Receptor; Sex Hormone; SERM; Immunoendocrinology; Dendritic Cells; Antigen-presenting cells; Cellular differentiation; Inflammation; Hematopoiesis
5.  Deficiency of type I IFN receptor in lupus-prone NZM 2328 mice decreases dendritic cell numbers and activation and protects from disease 1 
Type I interferons are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear antibody levels are greatly attenuated in NZM 2328 mice deficient in type I IFN receptors (IFNAR). To determine if the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2 and 5 month-old (clinically healthy) female NZM and NZM-IFNAR-/- mice. Numbers of activated CD40hi plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2 month-old NZM but not NZM-IFNAR-/- mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR-/- spleens in 5 month-old mice were significantly decreased in size and contained reduced numbers of conventional DC (cDC) subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR-/- DC analyzed directly ex vivo expressed significantly less CD40, CD86 and PDL1 than NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR-/- DC produced less IL-12p40/70 and TNFα than NZM DC. The limited IFNAR-/- DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of antigen presentation competence, and pro-inflammatory function prior to onset of clinically apparent lupus disease.
PMCID: PMC2766036  PMID: 19812195
Systemic lupus erythematosus; dendritic cells; autoimmunity; cell activation; cell differentiation
6.  Dehydroepiandrosterone in systemic lupus erythematosus 
Current rheumatology reports  2008;10(4):286-291.
Dehydroepiandrosterone (DHEA) is a weak androgen that exerts pleomorphic effects on the immune system. The hormone has no known receptor, and consequently, the mechanism of action of DHEA on immunocompetent cells remains poorly understood. Interestingly, serum levels of DHEA are decreased in patients with inflammatory disease including lupus, and these levels seem to inversely correlate with disease activity. Following encouraging studies demonstrating beneficial effects of DHEA supplementation in murine lupus models, a number of clinical studies have tested the effect of DHEA administration in lupus patients. DHEA treatment could improve patient’s overall quality of life assessment measures and glucocorticoid requirements in some lupus patients with mild to moderate disease, however, the effect of DHEA on disease activity in lupus patients remains controversial. Long term safety assessment studies are required in light of the reported effect of DHEA supplementation in lowering HDL cholesterol in lupus patients.
PMCID: PMC2701249  PMID: 18662508
7.  Regulation of dendritic cell differentiation and function by estrogen receptor ligands 
Cellular immunology  2008;252(1-2):81-90.
Estrogen receptor (ER) ligands can modulate innate and adaptive immunity and hematopoiesis, which may explain the clear sex differences in immune responses during autoimmunity, infection or trauma. Dendritic cells (DC) are antigen-presenting cells important for initiation of innate and adaptive immunity, as well as immune tolerance. DC progenitors and terminally differentiated DC express ER, indicating the ER ligands may regulate DC at multiple developmental and functional stages. Although there are profound differences in innate immunity between males and females or upon systemic imposition of sex hormones, studies are just beginning to link these differences to DC. Our and others studies demonstrate that estradiol and other ER ligands regulate the homeostasis of bone marrow myeloid and lymphoid progenitors of DC, as well as DC differentiation mediated by GM-CSF and Flt3 Ligand. Since DC have a brief lifespan, these data suggest that relatively short exposures to ER ligands in vivo will alter DC numbers and intrinsic functional capacity related to their developmental state. Studies in diverse experimental models also show that agonist and antagonist ER ligands modulate DC activation and production of inflammatory mediators. These findings have implications for human health and disease since they suggest that both DC development and functional capacity will be responsive to the physiological, pharmacological and environmental ER ligands to which an individual is exposed in vivo.
PMCID: PMC2593859  PMID: 18279845
Estrogen; Estrogen Receptor; Sex Hormone; SERM; Immunoendocrinology; Dendritic Cells; Antigen-presenting cells; cellular differentiation
8.  The Immune Response to Herpes Simplex Virus Type 1 Infection in Susceptible Mice Is a Major Cause of Central Nervous System Pathology Resulting in Fatal Encephalitis▿ †  
Journal of Virology  2008;82(14):7078-7088.
This study was undertaken to investigate possible immune mechanisms in fatal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brain stem lesions of primarily F4/80+ macrophages and Gr-1+ neutrophils detectable by magnetic resonance imaging as early as day 6 postinfection (p.i.). Depletion of macrophages and neutrophils significantly enhanced the survival of infected 129 mice. Immunodeficient B6 (IL-7R−/− Kitw41/w41) mice lacking adaptive cells (B6-E mice) and transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control nontransplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 or B6 bone marrow. Acyclovir treatment of 129 mice beginning on day 4 p.i. (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brain stem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.
PMCID: PMC2446972  PMID: 18480436
9.  Invariant Chain–independent Function of H-2M in the Formation of Endogenous Peptide–Major Histocompatibility Complex Class II Complexes In Vivo  
Efficient loading of major histocompatibility complex class II molecules with peptides requires the invariant chain (Ii) and the class II–like molecule H-2M. Recent in vitro biochemical studies suggest that H2-M may function as a chaperone to rescue empty class II dimers. To test this hypothesis in vivo, we generated mice lacking both Ii and H-2M (Ii−/−M−/−). Antigen presenting cells (APCs) from Ii−/−M−/− mice, as compared with APCs from Ii−/− mice, exhibit a significant reduction in their ability to present self-peptides to a panel of class II I-Ab–restricted T cells. As a consequence of this defect in the loading of self peptides, CD4+ thymocyte development is profoundly impaired in Ii−/−M−/− mice, resulting in a peripheral CD4+ T cell population with low levels of T cell receptor expression. These findings are consistent with the idea that H-2M functions as a chaperone in the peptide loading of class II molecules in vivo.
PMCID: PMC2212101  PMID: 9432982

Results 1-9 (9)