The thymus is one of the primary immune organs in childhood. During embryonic development, the migration of the thymus from the cervical region to the mediastinum coincides with the formation of other structures in the anterior cervical region, which can result in anomalous thymic locations. Among these, the most frequent are cervical remnants of accessory thymic tissue along the normal migration path and thymic extensions that project beyond their usual location. Ectopic locations, which deviate from the normal embryological course, are less common. Radiologists must recognize these variants and their imaging manifestations to avoid misdiagnosis and incorrect interventions. This article aims to review and illustrate, using imaging, the embryology, normal development, anatomy, and the most common locations of thymic tissue outside its normal position in the anterior mediastinum in children.

Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution, but the underlying cellular and molecular mechanisms remain unknown. We show here that thymic mesenchymal stromal cells (tMSCs) have a higher tendency to differentiate into adipocytes and melanocortin-2 receptor accessory protein (MRAP) is a potential driver of tMSCs adipogenesis. Furthermore, we discover that thymosin-α1 promotes MRAP expression in tMSCs through FoxO1 signaling pathway. Additionally, the proportion of tMSCs increase in older mice compared to young mice. Importantly, MRAP is also necessary for human thymic MSCs to differentiate into adipocytes when exposed to thymosin-α1. Single-cell RNA-seq analysis of human thymus revealed an accumulation of tMSCs and adipocytes during aging, indicating a strong potential for adipogenic differentiation in age-related thymic involution. Thus, we have revealed MRAP as a key factor in promoting thymic MSCs adipogenesis triggered by thymosin-α1 and FoxO1 pathway, which may serve as potential target to hinder adiposity in age-related thymic involution.

We point out the issue of differential diagnosis regarding the finding of ectopically localised thymic tissue (a thymic cyst) in the neck. Thymic tissue can be found anywhere along its developmental tract of descent, from the angle of the mandible to the upper mediastinum. Disruption of the thymic descent can result in ectopically/abnormally localised islets of accessory thymic tissue, which may undergo cystic changes, as described in a case report by Sun et al. This anatomical variation of the thymus may be clinically misinterpreted as a neoplasm or other congenital anomalies as a branchial cyst, lymphatic malformation or cystic hygroma. The present editorial focuses on the challenge of establishing a diagnosis of ectopically localised tissue of thymus often presented as a lateral cervical mass, especially in the case of cystic variation/degeneration of this thymic tissue. We summarise hypotheses on the origin of such congenital cervical thymic cysts from the point of view of evolutionary history and embryology. We also discuss lesser-known facts about the anatomy, histopathology and developmental biology of the thymus as one of the most enigmatic organs in the human body.

Interleukin-27 (IL-27) is able to inhibit HIV-1 replication in peripheral blood mononuclear cells (PBMCs), macrophages, and dendritic cells. Here, we identify that IL-27 can produce opposing effects on HIV-1 replication in PBMCs and that the HIV-1 restriction factor BST-2/Tetherin is involved in both inhibitory and enhancing effects on HIV-1 infection induced by IL-27. IL-27 inhibited HIV-1 replication when added to cells 2 h after infection, promoting the prototypical BST-2/Tetherin-induced virion accumulation at the cell membrane of HIV-1-infected PBMCs. BST-2/Tetherin gene expression was significantly upregulated in the IL-27-treated PBMCs, with a simultaneous increase in the number of BST-2/Tetherin+ cells. The silencing of BST-2/Tetherin diminished the anti-HIV-1 effect of IL-27. In contrast, IL-27 increased HIV-1 production when added to infected cells 4 days after infection. This enhancing effect was prevented by BST-2/Tetherin gene knockdown, which also permitted IL-27 to function again as an HIV-1 inhibitory factor. These contrasting roles of IL-27 were associated with the dynamic of viral production, since the IL-27-mediated enhancement of virus replication was prevented by antiretroviral treatment of infected cells, as well as by keeping cells under agitation to avoid cell-to-cell contact. Likewise, inhibition of CD11a, an integrin associated with HIV-1 cell-to-cell transmission, abrogated the IL-27 enhancement of HIV-1 production. Our findings illustrate the complexity of the HIV-1-host interactions and may impact the potential therapeutic use of IL-27 and other soluble mediators that induce BST-2/Tetherin expression for HIV-1 infection. IMPORTANCE Here, we describe new findings related to the ability of the cytokine IL-27 to regulate the growth of HIV-1 in CD4+ T lymphocytes. IL-27 has long been considered a potent inhibitor of HIV-1 replication, a notion based on several reports showing that this cytokine controls HIV-1 infection in peripheral blood mononuclear cells (PBMCs), monocyte-derived macrophages, and dendritic cells. However, our present results are contrary to the current knowledge that IL-27 acts only as a powerful downregulator of HIV-1 replication. We observed that IL-27 can either prevent or enhance viral growth in PBMCs, an outcome dependent on when this cytokine is added to the infected cells. We detected that the increase of HIV-1 dissemination is due to enhanced cell-to-cell transmission with the involvement of the interferon-induced HIV-1 restriction factor BST-2/Tetherin and CD11a (LFA-1), an integrin that participates in formation of virological synapse.

The immune response plays a key role in the disease development of the organism, while immune function serves as an important indicator for animal models evaluation. The tree shrew (Tupaia belangeri chinensis), as a new laboratory animal with a close genetic relationship with primates, has been used to construct various disease models. However, the immune system of tree shrews, especially anatomical descriptions of lymph nodes, is still relatively unknown. In this study, a total of 16 different lymph nodes were identified, including superficial lymph nodes and deep lymph nodes. Superficial lymph nodes were located in the head and neck region (submandibular lymph node, parotid lymph node, deep and superficial cervical lymph nodes) and at the forelimb (axillary and accessory axillary lymph nodes, subscapular lymph node) and hindlimb (popliteal, sciatic, and inguinal lymph nodes). Deep lymph nodes comprise mediastinal lymph nodes located in thoracic cavity and abdominal lymph nodes that are mainly located in each mesentery (mesenteric, gastric, pancreatic-duodenal, renal lymph nodes) or along the major vessels (iliac lymph nodes). In addition, we described the spleen and thymus of the tree shrew, as well as two lymphoid tissues in the top wall of the nasal cavity and the oropharynx. This study mainly describes the tree shrew immune system from an anatomical and histopathological perspective and provides fundamental research references for the establishment of various animal models of tree shrews.

T cell receptor (TCR) signaling influences multiple aspects of CD4+ and CD8+ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.

Cartilaginous fish are located at a pivotal point in phylogeny where the adaptive immune system begins to resemble that of other, more-derived jawed vertebrates, including mammals. For this reason, sharks and other cartilaginous fish are ideal models for studying the natural history of immunity. Insights from such studies may include distinguishing the (evolutionarily conserved) fundamental aspects of adaptive immunity from the (more recent) accessory. Some lymphoid tissues of sharks, including the thymus and spleen, resemble those of mammals in both appearance and function. The cartilaginous skeleton of sharks has no bone marrow, which is also absent in bony fish despite calcified bone, but cartilaginous fish have other Leydig's and epigonal organs that function to provide hematopoiesis analogous to mammalian bone marrow. Conserved across all vertebrate phylogeny in some form is gut-associated lymphoid tissues, or GALT, which is seen from agnathans to mammals. Though it takes many forms, from typhlosole in lamprey to Peyer's patches in mammals, the GALT serves as a site of antigen concentration and exposure to lymphocytes in the digestive tract. Though more complex lymphoid organs are not present in agnathans, they have several primitive tissues, such as the thymoid and supraneural body, that appear to serve their variable lymphocyte receptor-based adaptive immune system. There are several similarities between the adaptive immune structures in cartilaginous and bony fish, such as the thymus and spleen, but there are mechanisms employed in bony fish that in some instances bridge their adaptive immune systems to that of tetrapods. This review summarizes what we know of lymphoid tissues in cartilaginous fishes and uses these data to compare primary and secondary tissues in jawless, cartilaginous, and bony fishes to contextualize the early natural history of vertebrate mucosal immune tissues.

DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and whole-body imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development.

Human T cell leukemia virus type 1 (HTLV-1) is the ethological agent of adult T cell leukemia/lymphoma (ATLL) and a number of lymphocyte-mediated inflammatory conditions, including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 orf-I encodes two proteins, p8 and p12, whose functions in humans are to counteract innate and adaptive responses and to support viral transmission. However, the in vivo requirements for orf-I expression vary in different animal models. In macaques, the ablation of orf-I expression by mutation of its ATG initiation codon abolishes the infectivity of the molecular clone HTLV-1p12KO In rabbits, HTLV-1p12KO is infective and persists efficiently. We used humanized mouse models to assess the infectivity of both wild-type HTLV-1 (HTLV-1WT) and HTLV-1p12KO We found that NOD/SCID/γC-/- c-kit+ mice engrafted with human tissues 1 day after birth (designated NSG-1d mice) were highly susceptible to infection by HTLV-1WT, with a syndrome characterized by the rapid polyclonal proliferation and infiltration of CD4+ CD25+ T cells into vital organs, weight loss, and death. HTLV-1 clonality studies revealed the presence of multiple clones of low abundance, confirming the polyclonal expansion of HTLV-1-infected cells in vivo HTLV-1p12KO infection in a bone marrow-liver-thymus (BLT) mouse model prone to graft-versus-host disease occurred only following reversion of the orf-I initiation codon mutation within weeks after exposure and was associated with high levels of HTLV-1 DNA in blood and the expansion of CD4+ CD25+ T cells. Thus, the incomplete reconstitution of the human immune system in BLT mice may provide a window of opportunity for HTLV-1 replication and the selection of viral variants with greater fitness.IMPORTANCE Humanized mice constitute a useful model for studying the HTLV-1-associated polyclonal proliferation of CD4+ T cells and viral integration sites in the human genome. The rapid death of infected animals, however, appears to preclude the clonal selection typically observed in human ATLL, which normally develops in 2 to 5% of individuals infected with HTLV-1. Nevertheless, the expansion of multiple clones of low abundance in these humanized mice mirrors the early phase of HTLV-1 infection in humans, providing a useful model to investigate approaches to inhibit virus-induced CD4+ T cell proliferation.

Ectopic accessory thymic tissue usually presents as an asymptomatic neck mass found at any level corresponding to the embryonic descent of the thymus. This tissue may contain smaller or larger cysts. However, the exact pathogenesis of "enigmatic" cervical thymic cysts remains controversial. A 7-year-old boy was referred to our workplace for the evaluation of a cervical mass. An ultrasound suggested a multi-loculated cystic mass, while CT and MRI indicated a left-sided, anteriorly located cervical mass beneath the sternocleidomastoid muscle. Following the radiological findings, surgical excision revealed a cystic mass. The mass of tissue was covered by a capsule. In H&E staining, the cervical mass had the same structure as normal thymus. Additionally, immunohistochemical findings suggest that the cellular microenvironment of cervical thymus also displays a place for development of T-lymphocytes. Within the parenchyma multiple cysts lined with cytokeratin-positive thymic epithelial cells were found. Inside the cysts, there were CD68-positive multinucleated giant cells and cholesterol clefts. A tendency to cystic degeneration inside the thymic tissue occurs more often in cervical thymuses than in normally located ones. The reason for the formation of cysts is unknown. We summarized seven possible histological, embryological and evolutional backgrounds for the development of these thymic cysts.

The thymus is the main organ in the (anterior) (pre-vascular) mediastinum, playing a central role in the maintenance of both cellular and humoral immunity. The function of the thymus has been long underlooked due to its involution starting during young adulthood and unawareness regarding its immunological function. A variety of primary tumors and inflammatory/reactive/disreactive processes occur in the mediastinum and may involve the anterior-superior compartment and the thymus. Maldevelopment processes also take place in the pre-vascular compartment mediastinum. Although infective diseases do not currently represent the main processes in western countries, they may represent a diagnostic challenge in developing countries. The purpose of this review is to provide a short overview of the main thymic cellular components, their tumors, pseudotumors, in order to provide insights into their clinical setting and the features which assist pathologists in their differential diagnosis (DD). Specific differential diagnostic points are provided, both for "solid" tumors as well as for haematological malignancies, together with a morphological overview of cases of concern that occur in the anterior mediastinum. The main immunohistochemical characteristics of neoplastic/non-neoplastic pathology and updated specific references are also provided.

DNA repair consists of several cellular pathways which recognize and repair damaged DNA. The classical nonhomologous DNA end-joining (NHEJ) pathway repairs double-strand breaks in DNA. It is required for maturation of both B and T lymphocytes by supporting V(D)J recombination as well as B-cell differentiation during class switch recombination (CSR). Inactivation of NHEJ factors Ku70, Ku80, XRCC4, DNA ligase 4, DNA-PKcs, and Artemis impairs V(D)J recombination and blocks lymphocyte development. Paralogue of XRCC4 and XLF (PAXX) is an accessory NHEJ factor that has a significant impact on the repair of DNA lesions induced by ionizing radiation in human, murine, and chicken cells. However, the role of PAXX during development is poorly understood. To determine the physiological role of PAXX, we deleted part of the Paxx promoter and the first two exons in mice. Further, we compared Paxx-knockout mice with wild-type (WT) and NHEJ-deficient controls including Ku80- and Dna-pkcs-null and severe combined immunodeficiency mice. Surprisingly, Paxx-deficient mice were not distinguishable from the WT littermates; they were the same weight and size, fertility status, had normal spleen, thymus, and bone marrow. Paxx-deficient mice had the same number of chromosomal and chromatid breaks as WT mice. Moreover, Paxx-deficient primary B lymphocytes had the same level of CSR as lymphocytes isolated from WT mice. We concluded that PAXX is dispensable for normal mouse development.