Search

Background and Aims The G protein coupled receptor GPR15 is expressed on and functionally important for T cells homing to the large intestine. However, the precise mechanisms by which GPR15 controls gut homing have been unclear. Thus, we aimed to elucidate these mechanisms as well as to explore the potential of targeting GPR15 for interfering with T cell recruitment to the colon in inflammatory bowel disease [IBD]. Methods We used dynamic adhesion and transmigration assays, as well as a humanised in vivo model of intestinal cell trafficking, to study GPR15-dependent effects on gut homing. Moreover, we analysed GPR15 and integrin expression in patients with and without IBD, cross-sectionally and longitudinally. Results GPR15 controlled T cell adhesion to MAdCAM-1 and VCAM-1 upstream of α4β7 and α4β1 integrin, respectively. Consistently, high co-expression of these integrins with GPR15 was found on T cells from patients with IBD, and GPR15 also promoted T cell recruitment to the colon in humanised mice. Anti-GPR15 antibodies effectively blocked T cell gut homing in vitro and in vivo. In vitro data, as well as observations in a cohort of patients treated with vedolizumab, suggest that this might be more effective than inhibiting α4β7. Conclusions GPR15 seems to have a broad, but organ-selective, impact on T cell trafficking and is therefore a promising target for future therapy of IBD. Further studies are needed. [ABSTRACT FROM AUTHOR]

KD is an acute febrile illness and systemic vasculitis of unknown etiology among young children, which can cause coronary artery abnormalities and aneurysms (CAA) and is the leading cause of acquired heart disease among children in the US. Lactobacillus casei cell wall extract (LCWE) induces in mice a vasculitis following intraperitoneal injection defined by the activation of macrophages, dendritic cells and CD8+ cytotoxic T cells leading to aortitis, coronary arteritis, aneurysms and myocarditis that strongly mimic the immunopathology and the cardiac lesions observed in children with Kawasaki disease (KD). To address a potential pathogenic role of LCWE-specific T cells in human vascular inflammation, we studied the activation of circulating CD4+ and CD8+ T cells ex vivo in response to LCWE in 3 cohorts: (1) KD children 2-3 weeks after fever onset, (2) age-similar healthy children controls, (3) healthy adult controls. In all subjects studied, pro-inflammatory CD4+ and CD8+T cells responded to LCWE with no significant differences. Peripherally-induced regulatory T cells (iTreg) also responded to LCWE and potentially reverted to Th17, as suggested by the detection of IL-17 in culture supernatants. Central memory T cells were also detectable and were more abundant in adults. The potential homing to the vessels of LCWE-specific T cells was suggested by the expression of CCR6 and CD31. In conclusion, a non-pathogenic, LCWE-specific T cell repertoire could lead to KD depending upon priming conditions, genetic factors and immune activation by other antigens.

CD4+ and CD8+ T lymphocytes mediate most of the adaptive immune response against tumors. Naïve T lymphocytes specific for tumor antigens are primed in lymph nodes by dendritic cells. Upon activation, antigen-specific T cells proliferate and differentiate into effector cells that migrate out of peripheral blood into tumor sites in an attempt to eliminate cancer cells. After accomplishing their function, most effector T cells die in the tissue, while a small fraction of antigen-specific T cells persist as long-lived memory cells, circulating between peripheral blood and lymphoid tissues, to generate enhanced immune responses when re-encountering the same antigen. A subset of memory T cells, called resident memory T (TRM) cells, stably resides in non-lymphoid peripheral tissues and may provide rapid immunity independently of T cells recruited from blood. Being adapted to the tissue microenvironment, TRM cells are potentially endowed with the best features to protect against the reemergence of cancer cells. However, when tumors give clinical manifestation, it means that tumor cells have evaded immune surveillance, including that of TRM cells. Here, we review the current knowledge as to how TRM cells are generated during an immune response and then maintained in non-lymphoid tissues. We then focus on what is known about the role of CD4+ and CD8+ TRM cells in antitumor immunity and their possible contribution to the efficacy of immunotherapy. Finally, we highlight some open questions in the field and discuss how new technologies may help in addressing them. [ABSTRACT FROM AUTHOR]

Summary: The spleen comprises defined microanatomical compartments that uniquely contribute to its diverse host defense functions. Here, we identify a vascular compartment within the red pulp of the spleen delineated by expression of the atypical chemokine receptor 4 (ACKR4) in endothelial cells. ACKR4-positive vessels form a three-dimensional sinusoidal network that connects via shunts to the marginal sinus and tightly surrounds the outer perimeter of the marginal zone. Endothelial cells lining this vascular compartment express ACKR4 as part of a distinct gene expression profile. We show that T cells enter the spleen largely through this peri-marginal sinus and initially localize extravascularly around these vessels. In the absence of ACKR4, homing of T cells into the spleen and subsequent migration into T cell areas is impaired, and organization of the marginal zone is severely affected. Our data delineate the splenic peri-marginal sinus as a compartment that supports spleen homing of T cells.

KD is an acute febrile illness and systemic vasculitis of unknown etiology among young children, which can cause coronary artery abnormalities and aneurysms (CAA) and is the leading cause of acquired heart disease among children in the US. Lactobacillus casei cell wall extract (LCWE) induces in mice a vasculitis following intraperitoneal injection defined by the activation of macrophages, dendritic cells and CD8+ cytotoxic T cells leading to aortitis, coronary arteritis, aneurysms and myocarditis that strongly mimic the immunopathology and the cardiac lesions observed in children with Kawasaki disease (KD). To address a potential pathogenic role of LCWE-specific T cells in human vascular inflammation, we studied the activation of circulating CD4+ and CD8+ T cells ex vivo in response to LCWE in 3 cohorts: (1) KD children 2–3 weeks after fever onset, (2) age-similar healthy children controls, (3) healthy adult controls. In all subjects studied, pro-inflammatory CD4+ and CD8+T cells responded to LCWE with no significant differences. Peripherally-induced regulatory T cells (iTreg) also responded to LCWE and potentially reverted to Th17, as suggested by the detection of IL-17 in culture supernatants. Central memory T cells were also detectable and were more abundant in adults. The potential homing to the vessels of LCWE-specific T cells was suggested by the expression of CCR6 and CD31. In conclusion, a non-pathogenic, LCWE-specific T cell repertoire could lead to KD depending upon priming conditions, genetic factors and immune activation by other antigens.

Background: Therapeutic strategies for patients with ulcerative colitis (UC) are based on patient- and disease-related factors in combination with drug characteristics but fail to predict success in individual patients. A considerable proportion of UC patients do not respond to the biological vedolizumab. Therefore, pretreatment biomarkers for therapeutic efficacy are urgently needed. Mucosal markers related to the integrin-dependent T lymphocyte homing could be potent predictors., Methods: We prospectively included 21 biological- and steroid-naive UC patients with moderate-to-severe disease activity planned to escalate therapy to vedolizumab. At week 0, before initiating treatment, colonic biopsy specimens were obtained for immunophenotyping and immunohistochemistry. Clinical and endoscopic disease activity were determined at week 16 after 4 infusions of vedolizumab. In addition, we retrospectively included 5 UC patients who were first treated with anti-tumor necrosis factor α before receiving vedolizumab to compare with biological-naive patients., Results: Abundance of α4β7 on more than 8% of all CD3+ T lymphocytes in colonic biopsies at baseline was predictive for responsiveness to vedolizumab (sensitivity 100%, specificity 100%). The threshold for the proportion of MAdCAM-1+ and PNAd+ of all venules in the biopsies predictive for responsiveness to vedolizumab was ≥2.59% (sensitivity 89%, specificity 100%) and ≥2.41% (sensitivity 61%, specificity 50%), respectively. At week 16, a significant decrease of α4β7+CD3+T lymphocytes was demonstrated in responders (18% [12%-24%] to 8% [3%-9%]; P = .002), while no difference was seen in nonresponders (4% [3%-6%] to 3%; P = .59)., Conclusions: UC responders to vedolizumab have a higher percentage of α4β7+CD3+ T lymphocytes and a higher proportion of MAdCAM-1+ venules in colonic biopsies than nonresponders before initiating therapy. Both analyses could be promising predictive biomarkers for therapeutic response and may lead to more patient tailored treatment in the future., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Adoptive cell transfer (ACT) is a powerful experimental approach to directly study T-cell-mediated immunity in vivo. In the rhesus macaque AIDS virus model, infusing simian immunodeficiency virus (SIV)-infected animals with CD8 T cells engineered to express anti-SIV T-cell receptor specificities enables direct experimentation to better understand antiviral T-cell immunity in vivo. Limiting factors in ACT experiments include suboptimal trafficking to, and poor persistence in, the secondary lymphoid tissues targeted by AIDS viruses. Previously, we redirected CD8 T cells to B-cell follicles by ectopic expression of the CXCR5 homing protein. Here, we modify peripheral blood mononuclear cell (PBMC)-derived CD8 T cells to express the CCR9 chemokine receptor, which induces preferential homing of the engineered cells to the small intestine, a site of intense early AIDS virus replication and pathology in rhesus macaques. Additionally, we increase in vivo persistence and overall systemic distribution of infused CD8 T cells, especially in secondary lymphoid tissues, by minimizing ex vivo culture/manipulation, thereby avoiding the loss of CD28/CD95 central memory T cells by differentiation in culture. These proof-of-principle results establish the feasibility of preferentially localizing PBMC-derived CD8 T cells to the small intestine and enables the direct experimental ACT-based assessment of the potential role of the quality and timing of effective antiviral CD8 T-cell responses to inhibit viral infection and subsequent replication in small intestine CD4 T cells. More broadly, these results support the engineered expression of homing proteins to direct CD8 T cells to target tissues as a means for both experimental and potential therapeutic advances in T-cell immunotherapies, including cancer. [ABSTRACT FROM AUTHOR]

Junctional adhesion proteins play important roles in controlling angiogenesis, vascular permeability and leukocyte trafficking. CD112 (nectin-2) belongs to the immunoglobulin superfamily and was shown to engage in homophilic and heterophilic interactions with a variety of binding partners expressed on endothelial cells and on leukocytes. Recent in vitro studies suggested that CD112 regulates human endothelial cell migration and proliferation as well as transendothelial migration of leukocytes. However, so far, the role of CD112 in endothelial cell biology and in leukocyte trafficking has not been elucidated in vivo. We found CD112 to be expressed by lymphatic and blood endothelial cells in different murine tissues. In CD112-deficient mice, the blood vessel coverage in the retina and spleen was significantly enhanced. In functional in vitro studies, a blockade of CD112 modulated endothelial cell migration and significantly enhanced endothelial tube formation. An antibody-based blockade of CD112 also significantly reduced T cell transmigration across endothelial monolayers in vitro. Moreover, T cell homing to the spleen was significantly reduced in CD112-deficient mice. Overall, our results identify CD112 as a regulator of angiogenic processes in vivo and demonstrate a novel role for CD112 in T cell entry into the spleen.

The role of integrin-mediated adhesion during T cell progenitor homing to and differentiation within the thymus is ill-defined, mainly due to functional overlap. To circumvent compensation, we disrupted the hematopoietic integrin regulator kindlin-3 in mice and found a progressive thymus atrophy that is primarily caused by an impaired homing capacity of T cell progenitors to the vascularized thymus. Notably, the low shear flow conditions in the vascular system at midgestation allow kindlin-3-deficient fetal liver-derived T cell progenitors to extravasate via pharyngeal vessels and colonize the avascular thymus primordium. Once in the thymus, kindlin-3 promotes intrathymic T cell proliferation by facilitating the integrin-dependent crosstalk with thymic antigen presenting cells, while intrathymic T cell migration, maturation into single positive CD4 and CD8 T cells and release into the circulation proceed without kindlin-3. Thus, kindlin-3 is dispensable for integrin-mediated T cell progenitor adhesion and signalling at low and indispensable at high shear forces.

Background: Among infants exposed to human immunodeficiency virus (HIV) type 1, mixed breastfeeding is associated with higher postnatal HIV-1 transmission than exclusive breastfeeding, but the mechanisms of this differential risk are uncertain.Methods: HIV-1-exposed Ugandan infants were prospectively assessed during the first year of life for feeding practices and T-cell maturation, intestinal homing (β7hi), activation, and HIV-1 coreceptor (CCR5) expression in peripheral blood. Infants receiving only breast milk and those with introduction of other foods before 6 months were categorized as exclusive and nonexclusive, respectively.Results: Among CD4+ and CD8+ T cells, the expression of memory, activation, and CCR5 markers increased rapidly from birth to week 2, peaking at week 6, whereas cells expressing the intestinal homing marker increased steadily in the central memory (CM) and effector memory T cells over 48 weeks. At 24 weeks, when feeding practices had diverged, nonexclusively breastfed infants showed increased frequencies and absolute counts of β7hi CM CD4+ and CD8+ T cells, including the HIV-1-targeted cells with CD4+β7hi/CCR5+ coexpression, as well as increased activation.Conclusions: The T-cell phenotype associated with susceptibility to HIV-1 infection (CCR5+, gut-homing, CM CD4+ T cells) was preferentially expressed in nonexclusively breastfed infants, a group of infants at increased risk for HIV-1 acquisition. [ABSTRACT FROM AUTHOR]

Tumor-induced immune suppression has mainly been studied in patients with advanced cancer. Despite the fact that they are most likely to benefit from immunotherapy, patients with early stage cancers were under-represented in these studies. We analyzed blood and tumor-derived T cells from patients with stage 1 ( n = 20), stage 2 ( n = 23) or stage 3 ( n = 1) breast cancer and found that, even early stage tumors induced T cell differentiation. Breast cancer patients had significantly more circulating CD8+ memory and fewer CD8+ naïve T cells than healthy controls ( n = 10). Up-regulation of CD69 and PD1 on cancer patient T cells suggests previous activation, and increased expression of the chemokine receptors CCR5 and CXCR3 on CD8+ T cells indicates that their homing capacity differs from that of healthy individuals. Comparison of blood-derived and tumor-associated T cells from patients with different metastatic status and tumor grades revealed that tumor progression and aggressiveness seem to favor the expansion of memory T cells over naive T cells. We have previously shown that immunosuppression in this patient population is stronger in the tumor than in the blood. Here, we report signs of exhaustion, such as loss of CD28, on tumor-associated as compared to blood-derived CD8+ T cells, despite the fact that tumor-associated T cells are predominantly effector memory cells and express high levels of CD69. The finding that the presence of a tumor potentially induces immunosenescence early during tumorigenesis indicates that efficient immunotherapy might be difficult even in patients with early stage cancer due to T cell exhaustion and tolerance. [ABSTRACT FROM AUTHOR]

Syngeneic graft vs. host disease (SGVHD) was first described as a graft vs. host disease-like syndrome that developed in rats following syngeneic bone marrow transplantation (BMT) and cyclosporin A (CsA) treatment. SGVHD can be induced by reconstitution of lethally irradiated mice with syngeneic bone marrow cells followed by 21 days of treatment with the immunosuppressive agent CsA. Clinical symptoms of the disease appear 2-3 wk following cessation of CsA therapy, and disease-associated inflammation occurs primarily in the colon and liver. CD4+ T cells have been shown to play an important role in the inflammatory response observed in the gut of SGVHD mice. Time-course studies revealed a significant increase in migration of CD4+ T cells into the colon during CsA therapy, as well as significantly elevated mRNA levels of TNF-α, proinflammatory chemokines, and cell adhesion molecules in colonic tissue of CsA-treated animals compared with BMT controls, as early as day 14 post-BMT. Homing studies revealed a greater migration of labeled CD4+ T cells into the gut of CsA-treated mice at day 21 post-BMT than control animals via CsA-induced upregulation of mucosal addressin cell adhesion molecule. This study demonstrates that, during the 21 days of immunosuppressive therapy, functional mechanisms are in place that result in increased homing of CD4+ T effector cells to colons of CsA-treated mice. [ABSTRACT FROM AUTHOR]

Abstract: More than 40 years after the discovery of vasoactive intestinal peptide (VIP), its transcriptome in the immune system has still not been completely elucidated. In an attempt to understand the biological role of this neuropeptide in immunity, we chose CD4 T cells as a cellular system. Agilent Mouse Whole Genome microarrays were hybridized with fluorescently labeled total RNA isolated from resting CD4 T cells cultured ±10−7 M VIP for 5h or PMA/ionomycin activated CD4 T cells cultured ±10−7 M VIP for 5h. These VIP-regulated transcriptomes were analyzed by Significance Analysis of Microarrays (SAM) and Ingenuity Pathway Analysis (IPA) software to identify relevant signaling pathways modulated by VIP in the absence and presence of T cell activation. In resting CD4 T cells, VIP-modulated 368 genes, ranging from 3.49 to −4.78-fold. In the PMA/ionomycin activated CD4 T cells, 326 gene expression levels were changed by VIP, ranging from 2.94 to −1.66-fold. IPA analysis revealed that VIP exposure alters cellular function through EGFR signaling in resting CD4 T cells, and modulates immediate early genes, Fos and CREM/ICER, in activated CD4 T cells. These gene expression changes are suggested to explain at a molecular level how VIP can regulate T cell homing to the gut and induce regulatory T cell generation. [Copyright &y& Elsevier]

Circulating T lymphocytes enter a tissue if they express appropriate chemokine receptors and adhesion molecules to engage ligands presented at this site. To aid rational development of T cell-based therapies for Hodgkin’s lymphoma (HL), we have assessed the expression and function of homing receptors on tumour-infiltrating T cells in HL and compared them with T cells from unaffected lymph nodes and colorectal cancer tissue. Chemokine receptors CXCR3, CXCR4 and CCR7 were expressed on a large proportion of T cells within HL tissue and mediated chemotaxis to purified chemokine. The corresponding ligands (CXCL10, CXCL12, CCL21) were expressed on the malignant cells and/or vascular endothelium. Adhesion molecules including CD62L were widely expressed on HL-derived T cells and their corresponding ligands were detected on vessels within the tumour. This homing phenotype was distinct from T cells isolated from colorectal cancer, but matched closely the phenotype of T cells from unaffected lymph nodes. Thus, T cell recruitment to HL resembles entry of naïve/central memory T cells into normal lymph nodes. This has important implications for current approaches to treat HL using T cells activated and expanded in vitro that lack CCR7 and CD62L expression. [ABSTRACT FROM AUTHOR]

Abstract: Natural Tregs play an essential role in controlling self-tolerance but the in vivo sites of Treg-mediated suppression remain controversial. We have previously reported the identification of distinct naïve and memory Treg populations in human circulating lymphocytes. Here we show that memory Tregs contain high proportions of inflammatory chemokine-expressing cells and comprise two populations that differ in the expression of the lymphoid chemokine receptor CCR7 and represent the counterparts of conventional CCR7+ central memory (CM) and CCR7− effector memory (EM) T cells. CM and EM Tregs exert comparable ex vivo suppressor functions but the EM population is more prominent among Tregs as compared to conventional CD4+ T cells, and is the main Treg subset found in ovarian tumors. Our data suggest that a division of labor between CM and EM Tregs ensures tolerance at lymphoid and peripheral locations including tumor sites. [Copyright &y& Elsevier]

Abstract: Influences of psychological stress on the acquired immune system have not consequently been investigated. We found acute psychological stress to cause an increase in CD56+ and CCR5+ effector T cells in the peripheral blood of healthy human subjects (N =22), while skin-homing CLA+ T cells decreased. At the same time, we observed a stress-induced decrease in CD45RA+/CCR7+ naive and CD45RA−/CCR7+ central memory T cells, while CD45RA−/CCR7− effector memory and CD45RA+/CCR7− terminally differentiated T cells increased. This T cell redistribution translated into an increase in T cells expressing perforin/granzyme B and in Epstein-Barr virus-specific, cytomegalovirus-specific and influenza virus-specific CD8+ T cells. Thus, acute stress seems to promote the retention of less mature T cells within lymphoid tissue or skin while effector-type T cells are mobilized into the blood in order to be able to rapidly migrate into peripheral tissues. [Copyright &y& Elsevier]

Immunological memory allows for rapid and effective protective immunity to previously encountered pathogens. New insights in understanding specific memory differentiation and function have now indicated that in addition to providing enhanced immunity, an important purpose of immunological memory is to provide immediate protection at all sites of the body, including non-lymphoid tissues. Effector memory CD8 T cells have the capacity to reside long-term at epithelial surfaces, where they allow for rapid containment of the invading pathogens at the local entry site and prevent systemic spreading and excessive immune responses. The accumulation of tissue-specific memory T cell subsets, together with cross-reactivity of these antigen-experienced T cells even to unrelated pathogens, provides flexibility and expansion of their specificity repertoire that over time greatly surpasses that of the declining naïve T cell populations. This review will discuss new insights into T cell memory. We will focus in particular on the generation and function of effector memory CD8 T cells at the intestinal mucosa, which represents one of the largest entry sites for pathogens. [ABSTRACT FROM AUTHOR]

The cutaneous lymphocyte-associated antigen (CLA) is a homing receptor expressed in a subpopulation of memory T lymphocytes that migrates to the skin and participates in different inflammatory processes. The aim of the study was to compare the T cell response to betalactams in both CLA+ and CLA− memory T cell subsets from subjects with non-immediate allergic reactions to these drugs. Three patients with a non-immediate reaction to penicillins were studied during their acute episodes. Peripheral blood mononuclear cells were isolated by Ficoll density gradient and were used for flow cytometry and lymphocyte transformation test assays. CD3+ cells were purified via high affinity negative selection columns. CD45RA+ and CD45RO+ subpopulations were obtained by magnetic sorting and the memory subpopulation was subdivided into CLA+ and CLA− fractions. These were cultured in triplicate together with feeder cells and different concentrations of amoxicillin and benzylpenicillin. In all cases, the proliferative responses to the drugs were confined to the CD45RO+CLA+ subpopulation. The CD45RO+CLA− subset showed no proliferative response to either drug at any concentration. We have shown that the in vitro memory to penicillins in non-immediate cutaneous allergic reactions to these drugs resides in the CD45RO+CD3+ subset expressing CLA, which enables these T cells to migrate to the skin. These findings may have relevance to understanding the involvement of T cells in allergic reactions to penicillins. [Copyright &y& Elsevier]

Recent advances in immunotherapy have revolutionized the treatment of cancer. The use of adoptive cell therapies (ACT) such as those based on tumor infiltrating lymphocytes (TILs) or genetically modified cells (transgenic TCR lymphocytes or CAR-T cells), has shown impressive results in the treatment of several types of cancers. However, cancer cells can exploit mechanisms to escape from immunosurveillance resulting in many patients not responding to these therapies or respond only transiently. The failure of immunotherapy to achieve long-term tumor control is multifactorial. On the one hand, only a limited percentage of the transferred lymphocytes is capable of circulating through the bloodstream, interacting and crossing the tumor endothelium to infiltrate the tumor. Metabolic competition, excessive glucose consumption, the high level of lactic acid secretion and the extracellular pH acidification, the shortage of essential amino acids, the hypoxic conditions or the accumulation of fatty acids in the tumor microenvironment (TME), greatly hinder the anti-tumor activity of the immune cells in ACT therapy strategies. Therefore, there is a new trend in immunotherapy research that seeks to unravel the fundamental biology that underpins the response to therapy and identifies new approaches to better amplify the efficacy of immunotherapies. In this review we address important aspects that may significantly affect the efficacy of ACT, indicating also the therapeutic alternatives that are currently being implemented to overcome these drawbacks., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The spleen comprises defined microanatomical compartments that uniquely contribute to its diverse host defense functions. Here, we identify a vascular compartment within the red pulp of the spleen delineated by expression of the atypical chemokine receptor 4 (ACKR4) in endothelial cells. ACKR4-positive vessels form a three-dimensional sinusoidal network that connects via shunts to the marginal sinus and tightly surrounds the outer perimeter of the marginal zone. Endothelial cells lining this vascular compartment express ACKR4 as part of a distinct gene expression profile. We show that T cells enter the spleen largely through this peri-marginal sinus and initially localize extravascularly around these vessels. In the absence of ACKR4, homing of T cells into the spleen and subsequent migration into T cell areas is impaired, and organization of the marginal zone is severely affected. Our data delineate the splenic peri-marginal sinus as a compartment that supports spleen homing of T cells. [Display omitted] • ACKR4 is expressed in the spleen by red pulp vessels surrounding the marginal zone • Vascular shunts connect the marginal and the ACKR4+ "peri-marginal" sinuses • Circulating T cells enter the spleen via the ACKR4+ "peri-marginal" sinuses • ACKR4 supports spleen entry of T cells and their ensuing migration into the PALSs Werth et al. describe an atypical chemokine receptor 4 (ACKR4)-positive "peri-marginal" sinus being a part of a closed segment of spleen microvasculature and the main site of T cell homing into the spleen. The expression of ACKR4 is required for optimal spleen entry of T cells and their subsequent migration into the periarteriolar lymphatic sheaths (PALSs). [ABSTRACT FROM AUTHOR]

We have studied CD4+ Th 1 T cell responses in Borna disease (BD), a virus-mediated immune disease of the central nervous system (CNS), and demonstrate the priming of virus-specific as well as autoreactive T cells specific for myelin antigens in the course of viral infection. The fate of these in vivo generated T cells was subsequently assessed by in vitro proliferation assays with lymphocytes from different lymphoid organs of diseased animals over a long period of time. Virus-specific T cell responses continuously decreased during the establishment of persistent infection and could no longer be detected after 5-6 months post infectionem, when inflammatory reactions in the brain had ceased. By contrast, autoantigen-specific T cells kept their ability to mount characteristic secondary responses--although at an overall rather low level-over long periods of time: these autoreactive T cells homed to a specific lymphoid organ, the perithymic lymph node. Our study thus describes for the first time a complete decline of virus-specific T cell memory in a persistent viral infection, and raises the question how long-lasting T cell autoreactivity is controlled. [ABSTRACT FROM AUTHOR]

The cutaneous lymphocyte-associated antigen (CLA) is a carbohydrate epitope present on memory/effector T cells that infiltrate inflamed skin. E-selectin is the ligand for CLA and is induced under inflammation on endothelial cells. CLA was originally postulated as a phenotype marker for skin-associated T cells. We studied the specific in vitro response to skinassociated allergens of CLA+and CLA-CD45RO+T cells in atopic dermatitis (AD) and contact dermatitis (CD), which represent two well-characterized T cell-mediated cutaneous allergic inflammations. Whereas CLA+T cells from AD patients preferentially responded to house dust mite (HDM) and CLA+T cells from nickel CD patients showed an increased response to nickel, CLA-T cells showed very little response in both cases. In contrast, tetanus toxoid, a systemically acting antigen, induced a proliferative response in both CLA+and CLA-cells. Interestingly the response to HDM in patients with asthma±AD was preferentially found in the CLA-subset indicating the involvement of different homing receptors for mucosal tissues. Moreover, CLA+T cells showed enhanced migration through activated human umbilical vein endothelial cell monolayers compared to CLA-T cells. The CLA binding to E-selectin is initially responsible for the extravasation that also involves VLA-4/VCAM-1 and LFA-1/ ICAM-1 interactions. We have recently identified IL-8 as an endothelial cell-derived chemokine and the IL-8 receptor type B which control CLA+T cell migration. Such a CLA-mediated migration would localize memory/effector T cells that respond to antigens and reach the body through inflamed skin. Our data support the existence of a regionalization of the immune system and in particular of the skin immune system. It may allow an efficient distribution of the immune defense to different sites of the body. [ABSTRACT FROM AUTHOR]

Junctional adhesion proteins play important roles in controlling angiogenesis, vascular permeability and leukocyte trafficking. CD112 (nectin-2) belongs to the immunoglobulin superfamily and was shown to engage in homophilic and heterophilic interactions with a variety of binding partners expressed on endothelial cells and on leukocytes. Recent in vitro studies suggested that CD112 regulates human endothelial cell migration and proliferation as well as transendothelial migration of leukocytes. However, so far, the role of CD112 in endothelial cell biology and in leukocyte trafficking has not been elucidated in vivo. We found CD112 to be expressed by lymphatic and blood endothelial cells in different murine tissues. In CD112-deficient mice, the blood vessel coverage in the retina and spleen was significantly enhanced. In functional in vitro studies, a blockade of CD112 modulated endothelial cell migration and significantly enhanced endothelial tube formation. An antibody-based blockade of CD112 also significantly reduced T cell transmigration across endothelial monolayers in vitro. Moreover, T cell homing to the spleen was significantly reduced in CD112-deficient mice. Overall, our results identify CD112 as a regulator of angiogenic processes in vivo and demonstrate a novel role for CD112 in T cell entry into the spleen. [ABSTRACT FROM AUTHOR]

KD is an acute febrile illness and systemic vasculitis of unknown etiology among young children, which can cause coronary artery abnormalities and aneurysms (CAA) and is the leading cause of acquired heart disease among children in the US. Lactobacillus casei cell wall extract (LCWE) induces in mice a vasculitis following intraperitoneal injection defined by the activation of macrophages, dendritic cells and CD8+ cytotoxic T cells leading to aortitis, coronary arteritis, aneurysms and myocarditis that strongly mimic the immunopathology and the cardiac lesions observed in children with Kawasaki disease (KD). To address a potential pathogenic role of LCWE-specific T cells in human vascular inflammation, we studied the activation of circulating CD4+ and CD8+ T cells ex vivo in response to LCWE in 3 cohorts: (1) KD children 2-3 weeks after fever onset, (2) age-similar healthy children controls, (3) healthy adult controls. In all subjects studied, pro-inflammatory CD4+ and CD8+T cells responded to LCWE with no significant differences. Peripherally-induced regulatory T cells (iTreg) also responded to LCWE and potentially reverted to Th17, as suggested by the detection of IL-17 in culture supernatants. Central memory T cells were also detectable and were more abundant in adults. The potential homing to the vessels of LCWE-specific T cells was suggested by the expression of CCR6 and CD31. In conclusion, a non-pathogenic, LCWE-specific T cell repertoire could lead to KD depending upon priming conditions, genetic factors and immune activation by other antigens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hsieh, Tremoulet, Burns, Noval Rivas, Arditi and Franco.)

The role of integrin-mediated adhesion during T cell progenitor homing to and differentiation within the thymus is ill-defined, mainly due to functional overlap. To circumvent compensation, we disrupted the hematopoietic integrin regulator kindlin-3 in mice and found a progressive thymus atrophy that is primarily caused by an impaired homing capacity of T cell progenitors to the vascularized thymus. Notably, the low shear flow conditions in the vascular system at midgestation allow kindlin-3-deficient fetal liver-derived T cell progenitors to extravasate via pharyngeal vessels and colonize the avascular thymus primordium. Once in the thymus, kindlin-3 promotes intrathymic T cell proliferation by facilitating the integrin-dependent crosstalk with thymic antigen presenting cells, while intrathymic T cell migration, maturation into single positive CD4 and CD8 T cells and release into the circulation proceed without kindlin-3. Thus, kindlin-3 is dispensable for integrin-mediated T cell progenitor adhesion and signalling at low and indispensable at high shear forces., Competing Interests: FM, SK, RR, AM, WJ, RP, CS, MS, MM No competing interests declared, RF Reviewing editor, eLife, (© 2018, Moretti et al.)

High endothelial venules (HEVs) are blood vessels especially adapted for lymphocyte trafficking which are normally found in secondary lymphoid organs such as lymph nodes (LN) and Peyer's patches. It has long been known that HEVs develop in non-lymphoid organs during chronic inflammation driven by autoimmunity, infection or allografts. More recently, HEVs have been observed in solid, vascularized tumors and their presence correlated with reduced tumor size and improved patient outcome. It is proposed that newly formed HEV promote antitumor immunity by recruiting naive lymphocytes into the tumor, thus allowing the local generation of cancerous tissue-destroying lymphocytes. Understanding how HEVs develop and function are therefore important to unravel their role in human cancers. In LN, HEVs develop during embryonic and early post-natal life and are actively maintained by the LN microenvironment. Systemic blockade of lymphotoxin-β receptor leads to HEV de-differentiation, but the LN components that induce HEV differentiation have remained elusive. Recent elegant studies using gene-targeted mice have demonstrated clearly that triggering the lymphotoxin-β receptor in endothelial cells (EC) induces the differentiation of HEV and that CD11c+dendritic cells play a crucial role in this process. It will be important to determine whether lymphotoxin-β receptor-dependent signaling in EC drives the development of HEV during tumorigenesis and which cells have HEV-inducer properties. This may reveal therapeutic approaches to promote HEV neogenesis and determine the impact of newly formed HEV on tumor immunity. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that membrane-tethered type-1 matrix metalloproteinase (MT1-MMP)-induced proteolysis of T cell CD44 is important for defining the migration and function of autoreactive T cells, including diabetogenic, insulin-specific and K(d)-restricted IS-CD8(+) cells. To confirm the importance of MT1-MMP proteolysis of CD44 in type 1 diabetes (T1D), the anti-diabetic effects of three MMP inhibitors (3(S)-2,2-dimethyl-4[4-pyridin-4-yloxy-benzenesulfonyl]-thiomorpholine-3-carboxylic acid hydroxamate [AG3340], 2-(4-phenoxyphenylsulfonylmethyl) thiirane [SB-3CT] and epigallocatechin-3-gallate [EGCG]) were compared using an adoptive diabetes transfer model in non-obese diabetic (NOD) mice. Only AG3340 was capable of inhibiting both the activity of MT1-MMP and the shedding of CD44 in T cells; and the transendothelial migration and homing of IS-CD8(+) T cells into the pancreatic islets. SB-3CT and EGCG were incapable of inhibiting T cell MT1-MMP efficiently. As a result, AG3340 alone, but not SB-3CT or EGCG, delayed the onset of transferred diabetes in NOD mice. In summary, the results of the present study emphasize that the MT1-MMP-CD44 axis has a unique involvement in T1D development. Accordingly, we suggest that a potent small-molecule MT1-MMP antagonist is required for the design of novel therapies for T1D.