Jared E. Knickelbein

Bio: Jared E. Knickelbein is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Herpes simplex virus & Cytotoxic T cell. The author has an hindex of 15, co-authored 47 publications receiving 1157 citations. Previous affiliations of Jared E. Knickelbein include University of Pittsburgh.

Noncytotoxic lytic granule-mediated CD8+ T cell inhibition of HSV-1 reactivation from neuronal latency.

Abstract: Reactivation of herpes simplex virus type 1 (HSV-1) from neuronal latency is a common and potentially devastating cause of disease worldwide. CD8+ T cells can completely inhibit HSV reactivation in mice, with interferon-gamma affording a portion of this protection. We found that CD8+ T cell lytic granules are also required for the maintenance of neuronal latency both in vivo and in ex vivo ganglia cultures and that their directed release to the junction with neurons in latently infected ganglia did not induce neuronal apoptosis. Here, we describe a nonlethal mechanism of viral inactivation in which the lytic granule component, granzyme B, degrades the HSV-1 immediate early protein, ICP4, which is essential for further viral gene expression.

Stratification of Antigen-presenting Cells within the Normal Cornea

Abstract: The composition and location of professional antigen presenting cells (APC) varies in different mucosal surfaces. The cornea, long considered an immune-privileged tissue devoid of APCs, is now known to host a heterogeneous network of bone marrow-derived cells. Here, we utilized transgenic mice that express enhanced green fluorescent protein (EGFP) from the CD11c promoter (pCD11c) in conjunction with immunohistochemical staining to demonstrate an interesting stratification of APCs within non-inflamed murine corneas. pCD11c+ dendritic cells (DCs) reside in the basal epithelium, seemingly embedded in the basement membrane. Most DCs express MHC class II on at least some dendrites, which extend up to 50 µm in length and traverse up 20 µm tangentially towards the apical surface of the epithelium. The DC density diminishes from peripheral to central cornea. Beneath the DCs and adjacent to the stromal side of the basement membrane reside pCD11c-CD11b+ putative macrophages that express low levels of MHC class II. Finally, MHC class IIpCD11c-CD11b+ cells form a network throughout the remainder of the stroma. This highly reproducible stratification of bone marrow-derived cells is suggestive of a progression from an APC function at the exposed corneal surface to an innate immune barrier function deeper in the stroma.

Inflammatory Mechanisms of Age-related Macular Degeneration.

Abstract: Late age-related macular degeneration (AMD), specifically central geographic atrophy (GA) and choroidal neovascularization (CVN),1 is the leading cause of irreversible vision loss in the elderly in the developed world.2 AMD is categorized as either i) non-neovascular, or dry, when CNV is not present, or ii) neovascular, or wet, when CNV is present. Increasing age is the most significant risk factor for AMD development.3 In the United States, AMD is more common in Caucasians, and smoking is strongly associated. The hallmark of AMD clinically is the presence of drusen situated under the retinal pigment epithelium (RPE). Drusen size is categorized as small (≤62μm), medium (63–124μm), or large (≥125μm), with presence of large drusen being a significant predictor of progression to late AMD and associated vision loss.4 The Age-Related Eye Disease Studies (AREDS and AREDS2) have shown that high-dose antioxidant and zinc supplementation delay the progression of AMD in moderate- and high-risk patients.5, 6 Anti-vascular endothelial growth factor (VEGF) treatment is the mainstay of therapy for wet AMD.7 Currently, there is no treatment for GA. While AMD pathogenesis is undoubtedly multifactorial, including the effects of aging and oxidative stress as well as genetic and environmental factors, significant evidence has emerged implicating inflammation and the immune system. The major role of the immune system is to identify and respond to physiologic insults, such as infection, malignancy, and tissue damage. Often this takes the form of robust inflammatory responses, such as those seen in various forms of uveitis, despite the potent down-regulatory immune environment within the eye.8 In AMD, immune dysregulation in the form of overt intraocular inflammation is not clinically apparent. It has been proposed that the role of inflammation is not always negative. The concept of parainflammation has been suggested to describe inflammatory responses to tissue stress that are intermediate between basal and robust inflammatory states and function in a reparative manner.9, 10 As AMD is not accompanied by an intense inflammatory reaction, it is possible that dysregulation of reparative parainflammatory mechanisms, in the context of the aging eye, lead to a low grade chronic inflammatory response and subsequent AMD pathology. This review will focus on the potential inflammatory mechanisms of AMD pathogenesis based on evidence from human studies.

Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia.

Abstract: Memory stem T cells (TSCMs) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. Hallmarks of autoimmune disease pathogenesis are abnormal CD4(+) and CD8(+) T cell activation. We investigated the TSCM subset in 55, 34, 43, and 5 patients with acquired aplastic anemia (AA), autoimmune uveitis, systemic lupus erythematosus, and sickle cell disease, respectively, as well as in 41 age-matched healthy controls. CD8(+) TSCM frequency was significantly increased in AA compared with healthy controls. An increased CD8(+) TSCM frequency at diagnosis was associated with responsiveness to immunosuppressive therapy, and an elevated CD8(+) TSCM population after immunosuppressive therapy correlated with treatment failure or relapse in AA patients. IFN-γ and IL-2 production was significantly increased in various CD8(+) and CD4(+) T cell subsets in AA patients, including CD8(+) and CD4(+) TSCMs. CD8(+) TSCM frequency was also increased in patients with autoimmune uveitis or sickle cell disease. A positive correlation between CD4(+) and CD8(+) TSCM frequencies was found in AA, autoimmune uveitis, and systemic lupus erythematosus. Evaluation of PD-1, CD160, and CD244 expression revealed that TSCMs were less exhausted compared with other types of memory T cells. Our results suggest that the CD8(+) TSCM subset is a novel biomarker and a potential therapeutic target for AA.

Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus

Abstract: Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It has been suggested that T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. Here we describe a unique memory T cell subset present after acute infection with herpes simplex virus that remained resident in the skin and in latently infected sensory ganglia. These T cells were in disequilibrium with the circulating lymphocyte pool and controlled new infection with this virus. Thus, these cells represent an example of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry.