Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression in 8p23.1.

A major goal of genetics research is to elucidate mechanisms explaining how genetic variation contributes to phenotypic variation. The genetic variants identified in genome-wide association studies (GWASs) generally explain only a small proportion of heritability of phenotypic traits, the so-called missing heritability problem. Recent evidence suggests that additional common variants beyond lead GWAS variants contribute to phenotypic variation; however, their mechanistic underpinnings generally remain unexplored.

IL-4 and IL-15 promotion of virtual memory CD8 T cells is determined by genetic background.

Virtual memory (VM) CD8 T cells are present in unimmunized mice, yet possess T-cell receptors specific for foreign antigens. To date, VM cells have only been characterized in C57BL/6 mice. Here, we assessed the cytokine requirements for VM cells in C57BL/6 and BALB/c mice.

Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development.

Vaccines, arguably the single most important intervention in improving human health, have exploited the phenomenon of immunological memory. The elicitation of memory T cells is often an essential part of successful long-lived protective immunity. Our understanding of T cell memory has been greatly aided by the development of TCR Tg mice and MHC tetrameric staining reagents that have allowed the precise tracking of antigen-specific T cell responses.

Distinct roles of Cdc42 in thymopoiesis and effector and memory T cell differentiation.

Cdc42 of the Rho GTPase family has been implicated in cell actin organization, proliferation, survival, and migration but its physiological role is likely cell-type specific. By a T cell-specific deletion of Cdc42 in mouse, we have recently shown that Cdc42 maintains naïve T cell homeostasis through promoting cell survival and suppressing T cell activation. Here we have further investigated the involvement of Cdc42 in multiple stages of T cell differentiation.

Bcl-2 allows effector and memory CD8+ T cells to tolerate higher expression of Bim.

As acute infections resolve, most effector CD8(+) T cells die, whereas some persist and become memory T cells. Recent work showed that subsets of effector CD8(+) T cells, identified by reciprocal expression of killer cell lectin-like receptor G1 (KLRG1) and CD127, have different lifespans. Similar to previous reports, we found that effector CD8(+) T cells reported to have a longer lifespan (i.

A major role for Bim in regulatory T cell homeostasis.

We have previously shown that regulatory T cells (Treg) accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanisms underlying the age-dependent accrual of Treg remain unclear. In this study, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, or from enhanced peripheral conversion.

Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis.

T-cell homeostasis is essential for normal functioning of the immune system. IL-7 receptor (IL-7R) and T-cell receptor (TCR) signaling are pivotal for T-cell homeostatic regulation. The detailed mechanisms regulating T-cell homeostasis and how IL-7R and TCR signaling are coordinated are largely unknown.

Immune responses to coiled coil supramolecular biomaterials.

Self-assembly has been increasingly utilized in recent years to create peptide-based biomaterials for 3D cell culture, tissue engineering, and regenerative medicine, but the molecular determinants of these materials' immunogenicity have remained largely unexplored. In this study, a set of molecules that self-assembled through coiled coil oligomerization was designed and synthesized, and immune responses against them were investigated in mice. Experimental groups spanned a range of oligomerization behaviors and included a peptide from the coiled coil region of mouse fibrin that did not form supramolecular structures, an engineered version of this peptide that formed coiled coil bundles, and a peptide-PEG-peptide triblock bioconjugate that formed coiled coil multimers and supramolecular aggregates.

STAT5 is critical to maintain effector CD8+ T cell responses.

During an immune response, most effector T cells die, whereas some are maintained and become memory T cells. Factors controlling the survival of effector CD4(+) and CD8(+) T cells remain unclear. In this study, we assessed the role of IL-7, IL-15, and their common signal transducer, STAT5, in maintaining effector CD4(+) and CD8(+) T cell responses.

Contracting the 'mus cells'--does down-sizing suit us for diving into the memory pool?

Maintenance of T-cell homeostasis is critical for normal functioning of the immune system. After thymocyte selection, T cells enter the peripheral lymphoid organs, where they are maintained as naive cells. Transient disruption of homeostasis occurs when naive T cells undergo antigen-driven expansion and acquire effector functions.

CD8 T cell-initiated vascular endothelial growth factor expression promotes central nervous system vascular permeability under neuroinflammatory conditions.

Dysregulation of the blood-brain barrier (BBB) is a hallmark feature of numerous neurologic disorders as diverse as multiple sclerosis, stroke, epilepsy, viral hemorrhagic fevers, cerebral malaria, and acute hemorrhagic leukoencephalitis. CD8 T cells are one immune cell type that have been implicated in promoting vascular permeability in these conditions. Our laboratory has created a murine model of CD8 T cell-mediated CNS vascular permeability using a variation of the Theiler's murine encephalomyelitis virus system traditionally used to study multiple sclerosis.

Gamma interferon signaling in macrophage lineage cells regulates central nervous system inflammation and chemokine production.

Intracranial (i.c.) infection of mice with lymphocytic choriomeningitis virus (LCMV) results in anorexic weight loss, mediated by T cells and gamma interferon (IFN-gamma).

Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis.

We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2(-/-) mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim(+/-)Bcl-2(-/-) mice, but were largely restored in Bim(-/-)Bcl-2(-/-) mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim(-/-), T cells.

Cutting Edge: Limiting amounts of IL-7 do not control contraction of CD4+ T cell responses.

During the acute T cell response most effector T cells die while some survive and become memory T cells. Selective expression of CD127 (IL-7Ralpha) on effector T cells has been proposed to engender their survival into the memory pool. We assessed the role of IL-7 in effector T cell survival using MHC class II tetramers to track a CD4+ T cell response following infection with a recombinant vaccinia virus (rVV-2W1S).

An adenoviral vector for probing promoter activity in primary immune cells.

Functional analysis of the DNA regulatory regions that control gene expression has largely been performed through transient transfection of promoter-reporter constructs into transformed cells. However, transformed cells are often poor models of primary cells. To directly analyze DNA regulatory regions in primary cells, we generated a novel adenoviral luciferase reporter vector, pShuttle-luciferase-GFP (pSLUG) that contains a promoterless luciferase cassette (with an upstream cloning site) for probing promoter activity, and a GFP expression cassette that allows for the identification of transduced cells.

Identification of molecular targets for immunotherapy of patients with head and neck squamous cell carcinoma.

To identify molecular targets for immunotherapy of head and neck squamous cell carcinoma (HNSCC) patients, we analyzed gene expression profile in matched tumor (HN) and normal fibroblast (FB) cell lines established from a HNSCC patient using microarray technique followed by real-time RT-PCR. Screening against a series of established normal and malignant cell lines followed by screening against a panel of normal human tissues led to the identification of 7 genes (AREG, CDH3, KLK10, NmU, SLPI, ANAX3 and MAL2), which were over-expressed at least 10-fold in tumors over any of the normal tissues. We determined the expression of mRNA encoding these genes against a panel of 15 HNSCC primary tumor samples.

Recombinant vaccinia virus expressing IL-2 generates effective anti-tumor responses in an orthotopic murine model of head and neck carcinoma.

We evaluated the efficacy of a replication-competent, attenuated recombinant vaccinia virus (rvv) expressing IL-2 as a tumor vaccine in an immunocompetent murine model of head and neck squamous cell carcinoma. We implanted oral tumors by injection of tumor cells (SCC VII/SF) into the floor of the mouth of the syngeneic C3H/HeJ mice. Previous studies with this model suggested the presence of tumor-induced immune suppression.