Heba Nowyhed

the nr4a nuclear receptor family member nr4a1 is strongly induced in thymocytes undergoing selection, and has been shown to control the development of treg cells; however the role of nr4a1 in cd8(+) t cells remains undefined. here we report a novel role for nr4a1 in regulating the development and frequency of cd8(+) t cells through direct transcriptional control of runx3. we discovered that nr4a1 recruits the corepressor, corest to suppress runx3 expression in cd8(+) t cells. loss of nr4a1… Show more

the nr4a nuclear receptor family member nr4a1 is strongly induced in thymocytes undergoing selection, and has been shown to control the development of treg cells; however the role of nr4a1 in cd8(+) t cells remains undefined. here we report a novel role for nr4a1 in regulating the development and frequency of cd8(+) t cells through direct transcriptional control of runx3. we discovered that nr4a1 recruits the corepressor, corest to suppress runx3 expression in cd8(+) t cells. loss of nr4a1 results in increased runx3 expression in thymocytes which consequently causes a 2-fold increase in the frequency and total number of intrathymic and peripheral cd8(+) t cells. our findings establish nr4a1 as a novel and critical player in the regulation of cd8 t cell development through the direct suppression of runx3. Show less

Abstract B cells are required for follicular Th (Tfh) cell development, as is the ICOS ligand
(ICOS-L); however, the separable contributions of Ag and ICOS-L delivery by cognate B
cells to Tfh cell development and function are unknown. We find that Tfh cell and germinal
center differentiation are dependent on cognate B cell display of ICOS-L, but only when Ag
presentation by the latter is limiting, with the requirement for B cell expression of ICOS-L
overcome by robust Ag… Show more

Abstract B cells are required for follicular Th (Tfh) cell development, as is the ICOS ligand
(ICOS-L); however, the separable contributions of Ag and ICOS-L delivery by cognate B
cells to Tfh cell development and function are unknown. We find that Tfh cell and germinal
center differentiation are dependent on cognate B cell display of ICOS-L, but only when Ag
presentation by the latter is limiting, with the requirement for B cell expression of ICOS-L
overcome by robust Ag delivery. These findings demonstrate that Ag-specific B cells ... Show less

To understand chronic inflammatory diseases such as
atherosclerosis, we require in-depth knowledge on immune-cell differentiation, function of
specific immune-cell subsets and endothelial cell-mediated extravasation. In this review, we
summarize a number of very recent observations on the pivotal function of NR4A nuclear
receptors in immunity and atherosclerosis.

ATP-binding cassette transporter G1 (ABCG1) plays a role in the intracellular transport of cholesterol. Invariant NKT (iNKT) cells are a subpopulation of T lymphocytes that recognize glycolipid Ags. In this study, we demonstrate that ABCG1 regulates iNKT cell development and functions in a cell-intrinsic manner. Abcg1(-/-) mice displayed reduced frequencies of iNKT cells in thymus and periphery. Thymic iNKT cells deficient in ABCG1 had reduced membrane lipid raft content, and showed impaired… Show more

ATP-binding cassette transporter G1 (ABCG1) plays a role in the intracellular transport of cholesterol. Invariant NKT (iNKT) cells are a subpopulation of T lymphocytes that recognize glycolipid Ags. In this study, we demonstrate that ABCG1 regulates iNKT cell development and functions in a cell-intrinsic manner. Abcg1(-/-) mice displayed reduced frequencies of iNKT cells in thymus and periphery. Thymic iNKT cells deficient in ABCG1 had reduced membrane lipid raft content, and showed impaired proliferation and defective maturation during the early stages of development. Moreover, we found that Abcg1(-/-) mice possess a higher frequency of Vβ7(+) iNKT cells, suggesting alterations in iNKT cell thymic selection. Furthermore, in response to CD3ε/CD28 stimulation, Abcg1(-/-) thymic iNKT cells showed reduced production of IL-4 but increased production of IFN-γ. Our results demonstrate that changes in intracellular cholesterol homeostasis by ABCG1 profoundly impact iNKT cell development and function. Show less

CD4 T helper (Th) cells that secrete interleukin (IL)-17 (Th17) complement the function of
Th1 and Th2 cells as a third effector lineage, with a distinct role in neutrophil recruitment
necessary for extracellular pathogen clearance and the promotion of certain autoimmune
conditions. We have previously demonstrated that natural Th17 (nTh17) cells develop within
the thymus in a manner similar to that of natural T regulatory (nTreg) cells (Marks et al., Nat.
Immunol. 2009)… Show more

CD4 T helper (Th) cells that secrete interleukin (IL)-17 (Th17) complement the function of
Th1 and Th2 cells as a third effector lineage, with a distinct role in neutrophil recruitment
necessary for extracellular pathogen clearance and the promotion of certain autoimmune
conditions. We have previously demonstrated that natural Th17 (nTh17) cells develop within
the thymus in a manner similar to that of natural T regulatory (nTreg) cells (Marks et al., Nat.
Immunol. 2009), with activation in response to an increase of self-antigen due to tissue ... Show less

Retinoic acid (RA) is a small molecule capable of shunting developing T cells away from the Th17 lineage and towards the Treg phenotype, making it a potentially useful therapeutic for autoimmune and inflammatory diseases. However, therapy can be complicated by systemic toxicity and unpredictable bioavailability, making a targeted drug delivery vehicle for local therapy desirable. A promising approach is the use of nanoparticles, which have been demonstrated to increase potency and decrease… Show more

Retinoic acid (RA) is a small molecule capable of shunting developing T cells away from the Th17 lineage and towards the Treg phenotype, making it a potentially useful therapeutic for autoimmune and inflammatory diseases. However, therapy can be complicated by systemic toxicity and unpredictable bioavailability, making a targeted drug delivery vehicle for local therapy desirable. A promising approach is the use of nanoparticles, which have been demonstrated to increase potency and decrease toxicity of therapies in a variety of disease models including Th17 mediated diseases. Nanoparticles can also be targeted to specific cell types via surface modification, further increasing the potential specificity of this approach. We therefore constructed a nanoparticulate drug delivery platform from poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating and releasing RA. Here we report the fabrication, characterization, and in vitro bioactivity of this platform. We demonstrate that RA containing PLGA nanoparticles suppress IL-17 production and ROR-γ(t) expression in T cells polarized towards the Th17 phenotype in vitro with similar potency to that of free drug. Furthermore, we show that these particles enhance TGF-β dependent Foxp3 expression and IL-10 production of T cells in vitro with similar potency to free RA. Finally, we demonstrate that T cells polarized towards the Th17 phenotype in the presence of free and nanoparticulate RA have similarly suppressed ability to induce IL-6 production by fibroblasts. Our findings demonstrate the feasibility of RA delivery via biodegradable nanoparticles and represent an exciting technology for the treatment of autoimmune and inflammatory diseases. Show less

Interleukin 17 (IL-17)-producing CD4(+) helper T cells (T(H)-17 cells) share a developmental relationship with Foxp3(+) regulatory T cells (T(reg) cells). Here we show that a T(H)-17 population differentiates in the thymus in a manner influenced by recognition of self antigen and by the cytokines IL-6 and transforming growth factor-beta (TGF-beta). Like previously described T(H)-17 cells, the T(H)-17 cells that developed in the thymus expressed the transcription factor RORgamma t and the IL-23… Show more

Interleukin 17 (IL-17)-producing CD4(+) helper T cells (T(H)-17 cells) share a developmental relationship with Foxp3(+) regulatory T cells (T(reg) cells). Here we show that a T(H)-17 population differentiates in the thymus in a manner influenced by recognition of self antigen and by the cytokines IL-6 and transforming growth factor-beta (TGF-beta). Like previously described T(H)-17 cells, the T(H)-17 cells that developed in the thymus expressed the transcription factor RORgamma t and the IL-23 receptor. These cells also expressed alpha(4)beta(1) integrins and the chemokine receptor CCR6 and were recruited to the lung, gut and liver. In the liver, these cells secreted IL-22 in response to self antigen and mediated host protection during inflammation. Thus, T(H)-17 cells, like T(reg) cells, can be selected by self antigens in the thymus. Show less