Peripheral Non-lymphoid Tissues Research Articles

Loss of local innervation induces lymph node expansion

Peripheral lymphoid and non‐lymphoid tissues receive direct innervation via the nervous system but the relevance of neural input for the mounting of immune responses remains largely unknown. Ablating local innervation to popliteal lymph nodes (popLNs) by unilateral surgical ligation of the sciatic nerve led to footpad edema and dramatic expansion of popLNs due to an increase in cellularity in the ipsilateral side. In contrast, local surgeries leaving popLNs innervated, such as femoral denervation or sciatic denervation downstream of the popliteal fossa, did not generate nodal expansion. The increase in lymph node cellularity could be attributed to B cell proliferation and was associated with enhanced lymphocyte homing from the blood while leukocyte egress into efferent lymph remained unchanged. Homing was a critical factor in this process since blocking leukocyte entry into the lymph node with antibodies directed against L‐selectin or both α4‐ and αL‐integrins ablated denervation‐induced nodal expansion. Higher levels of TNF‐α, IL‐17 and IL‐4 were detected in denervated lymph nodes, the latter of which was also observed by systemic or local sympathectomy. Thus, loss of neural input to lymph nodes resulted in increased cellularity which was dependent on leukocyte homing. These data provide evidence for an important role of direct neural innervation in the control of immune responses.Support or Funding InformationFunded by the German Research Foundation (Emmy Noether SCHE 1645/2‐1 and SFB914 projects B09 and Z03) and the European Research Council (CIRCODE, 635872)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Tissue-Resident Memory CD8+ T Cells: From Phenotype to Function.

Tissue-resident memory CD8+ T cells are an important first line of defense from infection in peripheral non-lymphoid tissues, such as the mucosal tissues of the respiratory, digestive, and urogenital tracts. This memory T cell subset is established late during resolution of primary infection of those tissues, has a distinct genetic signature, and is often defined by the cell surface expression of CD69, CD103, CD49a, and CD44 in both mouse and human studies. The stimuli that program or imprint the unique gene expression and cell surface phenotypes on TRM are beginning to be defined, but much work remains to be done. It is not clear, for example, when and where the TRM precursors receive these signals, and there is evidence that supports imprinting in both the lymph node and the peripheral tissue sites. In most studies, expression of CD49a, CD103, and CD69 on T cells in the tissues appears relatively late in the response, suggesting there are precise environmental cues that are not present at the height of the acute response. CD49a and CD103 are not merely biomarkers of TRM, they confer substrate specificities for cell adhesion to collagen and E-cadherin, respectively. Yet, little attention has been paid to how expression affects the positioning of TRM in the peripheral tissues. CD103 and CD49a are not mutually exclusive, and not always co-expressed, although whether they can compensate for one another is unknown. In fact, they may define different subsets of TRM in certain tissues. For instance, while CD49a+CD8+ memory T cells can be found in almost all peripheral tissues, CD103 appears to be more restricted. In this review, we discuss the evidence for how these hallmarks of TRM affect positioning of T cells in peripheral sites, how CD49a and CD103 differ in expression and function, and why they are important for immune protection conferred by TRM in mucosal tissues such as the respiratory tract.

E3 Ligase VHL Promotes Group 2 Innate Lymphoid Cell Maturation and Function via Glycolysis Inhibition and Induction of Interleukin-33 Receptor

Group 2 innate lymphoid cells (ILC2s) are a specialized subset of lymphoid effector cells that are critically involved in allergic responses; however, the mechanisms of their regulation remain unclear. We report that conditional deletion of the E3 ubiquitin ligase VHL in innate lymphoid progenitors minimally affected early-stage bone marrow ILC2s but causeda selective and intrinsic decrease in mature ILC2 numbers in peripheral non-lymphoid tissues, resulting in reduced type 2 immune responses. VHLdeficiency caused the accumulation of hypoxia-inducible factor 1α (HIF1α) and attenuated interleukin-33 (IL-33) receptor ST2 expression, which was rectified by HIF1α ablation or inhibition. HIF1α-driven expression of the glycolytic enzyme pyruvate kinase M2 downmodulated ST2 expression via epigenetic modification and inhibited IL-33-induced ILC2 development. Our study indicates that the VHL-HIF-glycolysis axis is essential for the late-stage maturation and function of ILC2s via targeting IL-33-ST2 pathway.

Unconventional or Preset αβ T Cells: Evolutionarily Conserved Tissue-Resident T Cells Recognizing Nonpeptidic Ligands

A majority of T cells bearing the αβ T cell receptor (TCR) are specific for peptides bound to polymorphic classical major histocompatibility complex (MHC) molecules. Smaller subsets of T cells are reactive toward various nonpeptidic ligands associated with nonpolymorphic MHC class-Ib (MHC-Ib) molecules. These cells have been termed unconventional for decades, even though only the composite antigen is different from the one seen by classical T cells. Herein, we discuss the identity of these particular T cells in light of the coevolution of their TCR and MHC-Ib restricting elements. We examine their original thymic development: selection on hematopoietic cells leading to the acquisition of an original differentiation program. Most of these cells acquire memory cell features during thymic maturation and exhibit unique patterns of migration into peripheral nonlymphoid tissues to become tissue resident. Thus, these cells are termed preset T cells, as they also display a variety of effector functions. They may act as microbial or danger sentinels, fight microbes, or regulate tissue homeostasis.

Role of Memory T Cells in Allograft Rejection and Tolerance.

Memory T cells are characterized by their low activation threshold, robust effector functions, and resistance to conventional immunosuppression and costimulation blockade. Unlike their naïve counterparts, memory T cells reside in and recirculate through peripheral non-lymphoid tissues. Alloreactive memory T cells are subdivided into different categories based on their origins, phenotypes, and functions. Recipients whose immune systems have been directly exposed to allogeneic major histocompatibility complex (MHC) molecules display high affinity alloreactive memory T cells. In the absence of any prior exposure to allogeneic MHC molecules, endogenous alloreactive memory T cells are regularly generated through microbial infections (heterologous immunity). Regardless of their origin, alloreactive memory T cells represent an essential element of the allograft rejection process and a major barrier to tolerance induction in clinical transplantation. This article describes the different subsets of alloreactive memory T cells involved in transplant rejection and examine their generation, functional properties, and mechanisms of action. In addition, we discuss strategies developed to target deleterious allospecific memory T cells in experimental animal models and clinical settings.

Abstract A057: CX3CR1 distinguishes three distinct migratory memory CD8 T cell subsets

Abstract CD8 T cells are crucial for the protection against tumors and intracellular pathogens via their ability to generate long-term memory. Memory T cells (TMem) are however not a homogenous population. Traditionally, blood-borne TMem have been sub-divided into central memory (TCM) and effector memory (TEM) cells based on different migration behaviors and cytotoxic potential. We recently discovered the existence of a novel subset of CD8 TMem that has unique migratory properties and a superior homeostatic self-renewal capacity. The hitherto unrecognized memory CD8 T cell subset is characterized by intermediate expression levels of CX3CR1, while classical TCM were CX3CR1−, and TEM were CX3CR1high. The fraction of CX3CR1int cells among antigen-experienced TMem was remarkably stable over the course of a year, while TEM gradually declined and TCM increased to be the largest subset by 10 months. Interestingly, CX3CR1int TMem had the highest proliferation rate of the three TMem subsets. While TCM and TEM were phenotypically stable over >10 weeks at steady state, CX3CR1int TMem not only self-renewed, but also gave rise to bonafide TCM. Consequently, CX3CR1int TMem contributed to the gradual increase in TCM. The newly identified CX3CR1int TMem displayed unique migratory properties. Unlike CX3CR1high TEM, CX3CR1int gradually acquired lymph node homing capability. Moreover, parabiosis experiments and analysis of recirculating memory cells in thoracic duct lymph revealed that CX3CR1int TMem, not TEM, are the predominant T cell subset surveying non-lymphoid peripheral tissues. Supported by a postdoctoral fellowship of the Cancer Research Institute Irvington Fellowship Program and a Rubicon fellowship (Netherlands Organization for Scientific Research, NWO) to CG, NIH T32 Training Grant in Hematology 5T32-HL07623-20 to EAM, NIH F31 grant CA171339 to SML, NIH T32 grant HL066987 to DA, the Ragon Institute of MGH, MIT and Harvard and NIH/NIAID RO1 AI069259, PO1 AI078897 and PO1 AI112521 to UHvA. Citation Format: Carmen Gerlach, E. Ashley Moseman, Scott M. Loughhead, David Alvarez, Anthonie J. Zwijnenburg, Lisette Waanders, Rohit Garg, Juan C. de la Torre, Ulrich H. von Andrian. CX3CR1 distinguishes three distinct migratory memory CD8 T cell subsets [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A057.

A role for CXCL17 in Protective Vaginal CD8+ T cell Immunity Against Genital Herpes Infection and Disease

Abstract Conventional memory CD8+ T cells include effector memory (TEM) and central memory (TCM) CD8+ T cell subsets that circulate through the blood to access lymphoid and non-lymphoid tissues in order to control peripheral infections. A distinct non-recirculating tissue-resident memory CD8+ T cell subset (CD8+ TRM) develops and is retained within peripheral non-lymphoid mucosal tissues. Chemokines play a crucial role as chemoattractants for conventional memory CD8+ T cells. However, the identity of the chemokines involved in the homing of tissue-specific mucosal resident CD8+ TRM cells remain to be fully elucidated. We screened several prominent mucosal chemokines to identify those relevant to viral infections in the vagina. This screen indicated that the mucosal chemokine CXCL17 is strongly expressed in the vagina. We used herpes simplex virus type 1 (HSV-1) to determine the role of CXCL17 in immunity in the vaginal mucosa. Following HSV-1 infection, CXCL17 is strongly induced in the vaginal mucosa, and its expression parallels an increase in the number of tissue-resident CXCR8+CD8+ TRM cells. These changes are associated with a decrease in genital herpes infection and disease. Furthermore, a CXCL17−/− mouse failed to contain genital herpes when infected with HSV-1. These results strongly suggest a pivotal role for CXCL17 in protective vaginal CD8+ T cell immunity.

Brain infiltrating CD8+ T lymphocytes in lupus-prone mice

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple organ systems including the skin, kidneys, spleen, lungs, and brain. Severe SLE often manifests with multiple psychiatric and neurological sequelae, and may be accompanied by CNS vasculitis. However, the cellular contributors to CNS disease in lupus patients remain poorly defined. Our data demonstrate a unique lymphocyte bias in the CNS of mice expressing multiple copies of Toll-like receptor 7 (TLR7[Tg], FcgRIIB-Yaa), which present with a lupus-like disease. Lupus-prone mice have a substantial population of infiltrating CD8+ T cells in the CNS, a bias that is not present in other peripheral lymphoid or non-lymphoid tissues. These animals exhibit blood-brain barrier damage and neuropathology in the presence of the infiltrating lymphocytes. However, genetic ablation of CD8+ T cells in lupus-prone mice by removal of the major histocompatibility complex (MHC) adaptor protein b2m results in aggravation of disease, suggesting the removal of a protective population. Circulating CD8+ T cells in lupus-prone mice display an activated phenotype, express a number of surface trafficking and adhesion molecules, and can home to the CNS. The endothelium of the brain, but not of other peripheral organs in these mice is activated, expressing adhesion markers complementary to those found on infiltrating CD8+ T cells. Our ongoing studies aim to elucidate specifically how these CD8+ T cells enter the CNS and further clarify their role in neuropathology. Our findings suggest a possible mechanism regulating CNS pathology that could have applicability to human neuropsychiatric manifestations of SLE.

CX3CR1 distinguishes three antigen-experienced CD8 T cell subsets with distinct migratory, functional and homeostatic properties

Abstract Following infection, pathogen-specific T cells differentiate into diverse short-lived effectors (TEff) that give rise to long-lived memory (TMem) subsets. These T cell fate decisions and lineage relationships are poorly understood, in part, because available subset-defining markers do not adequately reflect existing heterogeneities. Here, we report that CX3CR1 identifies three distinct CD8+ TEff and TMem subsets. CX3CR1 expression levels on TEff were indicative of TEff differentiation, and predictive of the magnitude and type of memory progeny. Classical central memory (TCM) and effector memory cells (TEM) were CX3CR1– and CX3CR1high, respectively. In addition, we identified a hitherto unrecognized CX3CR1int population. The fraction of CX3CR1int cells among antigen-experienced TMem was remarkably stable over the course of a year, while TEM gradually declined and TCM increased to be the largest subset by 10 months. Interestingly, CX3CR1int TMem had the highest proliferation rate of the three TMem subsets. While TCM and TEM were phenotypically stable over >10 weeks at steady state, CX3CR1int TMem not only self-renewed, but also gave rise to bonafide TCM. This suggests that CX3CR1int TMem may contribute to the gradual increase in TCM. In contrast, re-infection resulted in unidirectional differentiation from TCM to CX3CR1int TMem to TEM. The newly identified CX3CR1int TMem displayed unique migratory properties. Unlike CX3CR1high TEM, CX3CR1int gradually acquired lymph node homing capability. Moreover, parabiosis experiments and analysis of recirculating memory cells in thoracic duct lymph revealed that CX3CR1int TMem, not TEM, are the predominant T cell subset surveying non-lymphoid peripheral tissues.

Pro-lymphangiogenic properties of IFN-γ-activated human dendritic cells

Dendritic cells (DCs) play a crucial role in the initiation of adaptive immune responses. In addition, through the release of pro- and anti-angiogenic mediators, DCs are key regulators of blood vessel remodeling, a process that characterizes inflammation. Less information is available on the role of DCs in lymphangiogenesis. This study reports that human DCs produce VEGF-C, a cytokine with potent pro-lymphangiogenic activity when stimulated with IFN-γ. DC-derived VEGF-C was biologically active, being able to promote tube-like structure formation in cultures of human lymphatic endothelial cells (LECs). DCs co-cultured with IL-15-activated NK cells produced high levels of VEGF-C, suggesting a role for NK-DC cross-talk in peripheral lymphoid and non-lymphoid tissues in inflammation-associated lymphangiogenesis. Induction of VEGF-C by IFN-γ was detected also in other myeloid cells, such as blood-purified CD1c+ DCs, CD14+ monocytes and in monocyte-derived macrophages. In all these cell types, VEGF-C was found associated with the cell membrane by low affinity, heparan sulphate-mediated, interactions. Therefore, human DCs should be considered as new players in inflammation-associated lymphangiogenesis.

Treg Cell Differentiation: From Thymus to Peripheral Tissue.

Regulatory T cells (Tregs) are crucial mediators of self-tolerance in the periphery. They differentiate in the thymus, where interactions with thymus-resident antigen-presenting cells, an instructive cytokine milieu, and stimulation of the T cell receptor lead to the selection into the Treg lineage and the induction of Foxp3 gene expression. Once mature, Treg cells leave the thymus and migrate into either the secondary lymphoid tissues, e.g., lymph nodes and spleen, or peripheral nonlymphoid tissues. There is growing evidence that Treg cells go beyond the classical modulation of immune responses and also play important functional roles in nonlymphoid peripheral tissues. In this review, we summarize recent findings about the thymic Treg lineage differentiation as well as the further specialization of Treg cells in the secondary lymphoid and in the peripheral nonlymphoid organs.

Homeobox Transcription Factor VentX Regulates Differentiation and Maturation of Human Dendritic Cells

Dendritic cells (DCs) are specialized antigen presentation cells that play critical roles in the initiation and regulation of immune responses. The molecular determinants of DC differentiation and maturation are target of extensive investigation. VentX is a human homeobox transcriptional factor that regulates proliferation and differentiation of hematopoietic cells. In the current study, we report that ablation of VentX expression in monocytes significantly impaired their differentiation into DCs. Conversely, overexpression of VentX in monocytic THP1 cells accelerated their differentiation toward DCs. We showed that VentX regulates DC differentiation, in part, through modulating IL6 expression. Clinically, we found that VentX expression was elevated in intestinal lamina propria DCs (LPDCs) of inflamed mucosa from inflammatory bowel disease patients. Knockdown experiments suggested that VentX is essential for the maturation of LPDCs. In addition, corticosteroid treatment markedly decreased VentX expression in LPDCs and enforced expression of VentX counteracted the effects of corticosteroid on DCs maturation. Our data suggest that VentX is a critical transcriptional regulator of DC differentiation and maturation, and a potential target of immune regulation and therapy.

Open questions: a few that need answers in immunology

The cells of the immune system fall into two broad categories - innate and adaptive - with the cells of the innate immune system providing frontline defense by means of invariant receptors to conserved microbial components, and the B and T lymphocytes of the adaptive immune system, with highly variable somatically diversified receptors, providing reinforcement after selective proliferation in response to specific antigen. While this principle still holds, the ‘old’ view of these systems as developmentally separate and functionally distinct has been eroded, most recently and dramatically by the discovery of a whole new group of innate lymphoid cell subsets. Another development has been the increasing emphasis on studying immune responses in vivo in interaction with stromal components that are beginning to be seen as essential contributors to the development of immune responses, rather than just as matrix or scaffold components in lymphoid organs or non-lymphoid peripheral tissues. A major focus now is on immune defense at epithelial barriers and homeostatic coexistence with a healthy microbiota, as it is becoming increasingly clear that intestinal dysbiosis strongly influences immune responses even at distal sites. However, whether dysbiosis is a cause or consequence of dysregulated inflammatory responses remains to be unraveled. I outline below some of the open questions raised by these developments.

Plasmacytoid Dendritic Cells in Cutaneous Disorders

Skin immune surveillance is granted by a complex contingent of sentinel innate immune cells with antigen-presenting function. The latter include Langerhans cells (LCs), multiple subsets of dermal dendritic cells (DDCs), and dermal macrophages (DMs). As for other peripheral nonlymphoid tissues, the microenvironment of the normal skin is lacking plasmacytoid dendritic cells (PDCs), a circulating DCs subset that mainly populates primary and secondary lymphoid organs. PDCs accumulation in the skin is observed in different cutaneous inflammatory disorders, including autoimmunity and viral infection. This review will summarize current knowledge on the biology of skin DCs and will highlight the functional role of PDCs in the complex microenvironment of well-characterized cutaneous disease models.

Near-infrared (NIR) 영상기법을 이용한 생체 내 수지상세포의 이동

Matured dendritic cells (DCs) begin migration with their release from the bone marrow (BM) into the blood and subsequent traffic into peripheral lymphoid and non-lymphoid tissues. Throughout this long movement, migrating DCs must apply specialized skills to reach their target destination. Non-invasive in vivo cell-tracking techniques are necessary to advance immune cell-based therapies. In this study, we used a DiD cell-tracking solution for in vivo dendritic cell tracking in naive mice. We tracked DiD (non-invasive fluorescence dye)-labeled mature dendritic cells using the Near Infrared (NIR) imaging system in normal mice. We examined the immunophenotype of DiD-labeled cells compared with non-labelled mature DCs, and obtained time-serial images of NIR-DC trafficking after mouse footpad injection. In conclusion, we confirmed that DiD-labeled DCs migrated into the popliteal lymph node 24 h after the footpad injection. Here, these data suggested that the cell tracking system with the stable fluorescence dye DiD was useful as a cell tracking tool to advance dendritic cell-based immunotherapy.

Uropod elongation is a common final step in leukocyte extravasation through inflamed vessels

The efficient trafficking of immune cells into peripheral nonlymphoid tissues is key to enact their protective functions. Despite considerable advances in our understanding of cell migration in secondary lymphoid organs, real-time leukocyte recruitment into inflamed tissues is not well characterized. The conventional multistep paradigm of leukocyte extravasation depends on CD18 integrin-mediated events such as rapid arrest and crawling on the surface of the endothelium and transmigration through the endothelial layer. Using enhanced three-dimensional detection of fluorescent CD18 fusion proteins in a newly developed knockin mouse, we report that extravasating leukocytes (neutrophils, monocytes, and T cells) show delayed uropod detachment and become extremely elongated before complete transmigration across the endothelium. Additionally, these cells deposit CD18(+) microparticles at the subendothelial layer before retracting the stretched uropod. Experiments with knockout mice and blocking antibodies reveal that the uropod elongation and microparticle formation are the result of LFA-1-mediated adhesion and VLA-3-mediated cell migration through the vascular basement membrane. These findings suggest that uropod elongation is a final step in the leukocyte extravasation cascade, which may be important for precise regulation of leukocyte recruitment into inflamed tissues.

Tissue-Specific Homing of Immune Cells in Malignant Skin Tumors

Tissue-specific migration of immune cells involved both in physiological and pathological immune responses is a current research subject for medical science. Several homing molecules have been identified orchestrating extravasation of immune cells to certain peripheral non-lymphoid tissues such as gut, lung and skin. Regarding lymphocyte homing to skin, the first-line defense of human body cutaneous lymphocyte associated antigen (CLA) and a group of chemokine-chemokine receptor pairs are considered to be of crucial importance. The aim of the present review is to summarize existing knowledge about skin- and tumor-specific migration of immune cells playing a major pathogenetic role in host immune responses induced by non-lymphoid malignant skin tumors as well as in the development of primary cutaneous T-cell lymphomas (CTCL). Melanoma malignum, squamous and basal cell carcinoma evoke host immune responses and consequently a subset of reactive immune cells is recruited to site of the tumor. Regarding migratory process and exact functional role of these cells a growing number of data is available in literature. On the other hand tissue-specific immune cell homing is regarded as a key process in the pathogenesis of CTCL where malignant T-lymphocytes can be found in circulation and symptomatic skin. Hereby homing mechanism of malignant T-cells in mycosis fungoides and Sézary-syndrome as separate clinical entities of CTCL is discussed. A precise insight into the molecular background of skin- and tumor-specific immune cell migration can contribute to developing efficient vaccine therapies in non-lymphoid malignant skin tumors and beneficial treatment modalities in CTCL.

TSLP and Immune Homeostasis

In an immune system, dendritic cells (DCs) are professional antigen-presenting cells (APCs) as well as powerful sensors of danger signals. When DCs receive signals from infection and tissue stress, they immediately activate and instruct the initiation of appropriate immune responses to T cells. However, it has remained unclear how the tissue microenvironment in a steady state shapes the function of DCs. Recent many works on thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine that has the strong ability to activate DCs, provide evidence that TSLP mediates crosstalk between epithelial cells and DCs, involving in DC-mediated immune homeostasis. Here, we review recent progress made on how TSLP expressed within the thymus and peripheral lymphoid and non-lymphoid tissues regulates DC-mediated T-cell development in the thymus and T-cell homeostasis in the periphery.

Antigen nonspecific memory CD8 T cells expand and gain effector function in response to immunotherapy or to viral infection (131.28)

Abstract Memory CD8 T cells (CD44hi+) have a wide distribution in peripheral blood, secondary lymphoid and non-lymphoid tissues and are hallmarked by their ability to respond rapidly to antigenic re-challenge. We observed that systemic cytokine immunotherapy (IT) results in the marked expansion of memory CD8 T cells due to the preferential expansion of pre-existing memory T cells and not the conversion of naïve (CD44lo+) T cells to an activated phenotype. These CD8 T cells express NKG2D and have cytolytic activity; however, a lack of increased CD25 and PD-1 expression suggests that the expansion and activation are independent of TCR engagement. Studies of CD8 T cells from OT-1 TCR transgenic mice after IT demonstrated the increased lysis of ova-negative tumor targets; moreover, the OT-1 CD8 T cells possessed a memory phenotype and lacked CD25 expression in the absence of ova vaccination. To determine if memory CD8 T cells play a role in pathogenic situations, mice were infected with influenza and tissues were examined for the presence of CD25-NKG2D+ memory CD8 T cells. Interestingly, these cells expanded rapidly in the lungs of infected mice but not peripheral tissues, indicating that memory T cells may play a role in the clearance of pathogen, regardless of antigen specificity. These data suggest that resident tissue memory CD8 T cells may act in reserve as innate effectors and thus bridge the gap between adaptive and innate immunity in cancer immunotherapy and viral infections.

Persistent Viral Infection Elevates Central Nervous System MHC Class I through Chronic Production of Interferons

Persistence of even the stealthiest viruses can perturb immune function either to the benefit or detriment of the host. Lymphocytic choriomeningitis virus (LCMV) establishes lifelong, systemic persistence when introduced in utero or at birth. Despite a highly evolved host-pathogen relationship, LCMV cannot escape detection by the innate immune system, which results in chronic stimulation of the type 1 IFN pathway in adult carrier mice. In this study we demonstrate that IFN-beta is chronically up-regulated in peripheral lymphoid and nonlymphoid tissues (but not the CNS) of mice persistently infected from birth with LCMV and that dendritic cells (DCs) represent at least one source of IFN-beta. Interestingly, chronic stimulation of this innate pathway significantly elevated MHC class I expression in the CNS as well as the periphery. Elevated MHC I expression was dependent on IFN-alphabeta receptor but not MyD88-dependent signaling, as only genetic deletion of the former reduced MHC I to normal levels. An increase in circulating virus was also observed in the IFN-alphabeta receptor deficient carrier mice, signifying that type I IFN continually exerts anti-viral pressure during a LCMV carrier state. Finally, to determine whether heightened CNS MHC I could be therapeutically corrected, we purged LCMV carrier mice of their persistent infection using adoptive immunotherapy. This treatment significantly reduced CNS MHC I expression. Collectively, these data demonstrate that even a well adapted pathogen can chronically stimulate the innate immune system and consequently alter the expression of Ag presenting machinery in an immunologically specialized compartment like the CNS.