Tissue Homing Receptors Research Articles

High Dose Intravenous IgG Therapy Modulates Multiple NK Cell and T Cell Functions in Patients With Immune Dysregulation.

Intravenous immunoglobulin (IVIG) is an effective immunomodulatory treatment for immune dysregulation diseases. However, the mechanisms by which it reduces systemic inflammation are not well understood. NK cell cytotoxicity is decreased by IVIG in women with reduced fertility, but IVIG effects on NK cells in immune dysregulation are less clear. We hypothesized that IVIG modulation of lymphocyte function, especially in NK cells, is important for resolution of inflammation. Our aim was to identify IVIG-induced changes in a cohort of patients with Kawasaki disease (KD) and those that occur broadly in pediatric patients with various immune dysregulatory diseases. Peripheral blood mononuclear cells (PBMCs) of patients with KD or autoimmune/inflammatory diseases were phenotyped pre and post high dose IVIG treatment by flow cytometry. In KD patients, after IVIG infusion Treg cell frequency and the proportion of activated CD25+ immunoregulatory CD56bright NK cells was increased, and multiple lymphocyte subsets showed increased expression of the lymphoid tissue homing receptor CD62L. Importantly, IVIG treatment decreased the frequency of cells expressing the degranulation marker CD107a among cytotoxic CD56dim NK cells, which was reflected in a significant reduction in target cell killing and in decreased production of multiple pro-inflammatory mediators. Interestingly, the activating receptor CD336 was expressed on a higher proportion of CD56bright NK cells after IVIG in both KD and autoimmune/inflammatory patients while other NK receptors were increased differentially in each cohort. In autoimmune/inflammatory patients IVIG induced the proliferation marker CD71 on a higher percentage of CD56dim NK cells, and in contrast to KD patients, CD107a+ cells were increased in this subset. Furthermore, when PBMCs were stimulated ex vivo with IL-2 or Candida antigen in autologous plasma, more of the CD4+ T cells of KD patients expressed CD25 after IVIG therapy but fewer cytotoxic T cells were degranulated based on CD107a expression. In summary, IVIG treatment in patients with immune dysregulation has multiple effects, especially on NK cell subsets and CD4+ T cells, which are compatible with promoting resolution of inflammation. These novel findings provide insight into the immunomodulatory actions of IVIG in autoimmune and inflammatory conditions.

Single-Cell RNA Sequencing Reveals Tissue Compartment-Specific Plasticity of Mycosis Fungoides Tumor Cells.

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. While initially restricted to the skin, malignant cells can appear in blood, bone marrow and secondary lymphoid organs in later disease stages. However, only little is known about phenotypic and functional properties of malignant T cells in relationship to tissue environments over the course of disease progression. We thus profiled the tumor micromilieu in skin, blood and lymph node in a patient with advanced MF using single-cell RNA sequencing combined with V-D-J T-cell receptor sequencing. In skin, we identified clonally expanded T-cells with characteristic features of tissue-resident memory T-cells (TRM, CD69+CD27-NR4A1+RGS1+AHR+). In blood and lymph node, the malignant clones displayed a transcriptional program reminiscent of a more central memory-like phenotype (KLF2+TCF7+S1PR1+SELL+CCR7+), while retaining tissue-homing receptors (CLA, CCR10). The skin tumor microenvironment contained potentially tumor-permissive myeloid cells producing regulatory (IDO1) and Th2-associated mediators (CCL13, CCL17, CCL22). Given their expression of PVR, TNFRSF14 and CD80/CD86, they might be under direct control by TIGIT+CTLA4+CSF2+TNFSF14+ tumor cells. In sum, this study highlights the adaptive phenotypic and functional plasticity of MF tumor cell clones. Thus, the TRM-like phenotype enables long-term skin residence of MF cells. Their switch to a TCM-like phenotype with persistent skin homing molecule expression in the circulation might explain the multi-focal nature of MF.

059 Single-cell RNA sequencing reveals tissue compartment-specific plasticity of mycosis fungoides tumor cells

While mycosis fungoides (MF) is usually restricted to the skin during early disease, malignant cells can appear in blood, bone marrow and secondary lymphoid organs in later disease stages. However, only little is known about phenotypic and functional properties of malignant T cells in relationship to tissue environments over the course of disease progression. We thus profiled the tumor micromilieu in skin, blood and lymph node in a patient with advanced MF using single-cell RNA sequencing combined with V-D-J T-cell receptor sequencing. In skin, we identified clonally expanded T-cells with characteristic features of tissue-resident memory T-cells (TRM, CD69+CD27-NR4A1+RGS1+AHR+). In blood and lymph node, the malignant clones displayed a transcriptional program reminiscent of a more central memory-like phenotype KLF2+TCF7+S1PR1+SELL+CCR7+), while retaining tissue-homing receptors. The skin tumor microenvironment contained potentially tumor-permissive myeloid cells producing regulatory (IDO1) and Th2-associated mediators (CCL13, CCL17, CCL22). Given their expression of PVR, TNFRSF14 and CD80/CD86, they might be under direct control by TIGIT+CTLA4+CSF2+TNFSF14+ tumor cells. This work demonstrates adaptive phenotypic and functional plasticity of MF tumor cell clones. Thus, the TRM-like phenotype allows them to reside within the skin for long periods of time, while adopting a TCM-like phenotype with skin homing molecule retention in peripheral blood. Furthermore, understanding the mechanisms underlying the plasticity of MF cells could be relevant for the migratory behavior of regular memory T cells.

Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.

Characterization of γδ T Cell Effector/Memory Subsets Based on CD27 and CD45R Expression in Response to Mycobacterium bovis Infection.

Tuberculosis (TB) remains a leading cause of death from infectious diseases worldwide. Mycobacterium bovis is the causative agent of bovine TB and zoonotic TB infection. γδ T cells are known to participate in the immune control of mycobacterial infections. Data in human and nonhuman primates suggest that mycobacterial infection regulates memory/effector phenotype and adaptive immune functions of γδ T cells. To date, the impact of M. bovis infection on bovine γδ T cells and their effector and memory differentiation remains unknown. In this study, we show that circulating γδ T cells from M. bovis-infected cattle can be differentiated based on the expression of CD27, which is indicative of their capacity to respond to virulent M. bovis infection: CD27+ γδ T cells proliferated in response to M. bovis Ag and, thus, may comprise the adaptive γδ T cell compartment in cattle. We further show that bovine M. bovis-specific γδ T cells express surface markers characteristic of central memory T cells (CD45R-CD27+CD62Lhi) and that M. bovis-specific CD4 and γδ T cells both upregulate the expression of the tissue-homing receptors CXCR3 and CCR5 during infection. Our studies contribute significantly to our understanding of γδ T cell differentiation during TB infection and provide important insights into the link between phenotypic and functional subsets in the bovine. Accurate characterization of γδ T cell effector and memory-like responses induced during mycobacterial infection will contribute to improved strategies for harnessing the γδ T cell response in protection against TB for humans and animals.

Mucosal-Associated Invariant T Cells Are Depleted and Exhibit Altered Chemokine Receptor Expression and Elevated Granulocyte Macrophage-Colony Stimulating Factor Production During End-Stage Renal Disease.

End-stage renal disease (ESRD) is associated with an increased susceptibility to infectious diseases, including infection with Mycobacterium tuberculosis (Mtb). Mucosal-associated invariant T (MAIT) cells recognize vitamin B metabolites produced by many bacterial species, including Mtb, and may play an important role in providing protective immunity against tuberculosis infection in the lung. To date, little is known about MAIT cell frequency, phenotype, or function in ESRD patients. MAIT cells, identified by surface marker expression or MR1 tetramer binding, were characterized in 20 ESRD and 20 healthy control participants by multicolor flow cytometry. Ex vivo MAIT cell phenotype and cytokine production following PMA/ionomycin, IL-12/IL-18, or Escherichia coli stimulation were determined. Monocyte phenotype and plasma C-reactive protein/inflammatory cytokine levels were quantified by flow cytometry, ELISA, and multiplex bead array. Peripheral blood MAIT cells were significantly depleted among ESRD patients compared to controls by both phenotypic and tetramer analysis and exhibited a loss of CXCR3 expression coupled to increased expression of CCR6 and CXCR6. ESRD was also associated with a shift in MAIT PMA-induced cytokine production away from IFNγ production and toward granulocyte macrophage-colony stimulating factor (GM-CSF) secretion, and a loss of E. coli-stimulated tumor necrosis factor α expression. Loss of IFNγ expression was associated with a combination of age, alterations in Tbet and Eomes expression, and inflammatory plasma cytokine levels. The loss of peripheral blood MAIT cells and associated shifts in tissue homing receptor expression and GM-CSF production may contribute to an immune environment that is permissive to bacterial replication, particularly in the lungs.

014 The arylhydrocarbon receptor agonist 4-n-nonylphenol switches non-regulatory T cells into a regulatory phenotype

4-n-nonylphenol (NP), an arylhydrocarbon receptor (AhR)-agonist, was found to inhibit the induction of contact hypersensitivity (CHS) in mice via induction of regulatory T cells (Treg). Although dendritic cells were identified as one of the major targets for NP in its immunosuppressive features, it is unknown whether NP can directly affect T cells as well. To address this issue, non-regulatory T cells (CD4+CD25-) were isolated from trinitrochlorobenzene (TNCB)-sensitized mice and stimulated with NP or left untreated. After 48 hours cells were injected intravenously into naïve recipients which were sensitized after injection; Treg (CD4+CD25+) served as a control. Ear challenge with TNCB was significantly suppressed in mice injected with NP-treated cells comparable to the Treg control. In contrast, injection of untreated CD4+CD25- did not affect CHS in the recipients. Flow cytometry analysis revealed a strong induction of the Treg markers Foxp3 and Garp in response to NP, suggesting that NP shifts non-regulatory T cells into a regulatory phenotype. However, NP-Treg did not suppress the elicitation phase of CHS since the ear challenge response was not suppressed upon intravenous injection of NP-Treg into already sensitized mice. When injected subcutaneously into the ears of sensitized mice before challenge the ear swelling response was significantly reduced, indicating that NP-Treg upon intravenous injection may migrate into the lymph nodes but not into the skin. This may be due to the expression of specific tissue homing receptors. To prove whether NP induces Treg also in the human system CD4+CD25- cells were isolated from peripheral blood mononuclear cells, incubated with NP and subjected to an in vitro suppression assay. NP-Treg suppressed the proliferative capacity of the responder cells, whereas unstimulated CD4+CD25- did not. Together this implies that activation of the AhR switches non-regulatory T cells into a regulatory phenotype which is functionally suppressive.

Validation of RUNX1 as a potential target for treating circadian clock-induced obesity through preventing migration of group 3 innate lymphoid cells into intestine

The impact of unrhythmic circadian clock on obesity has started to be increasingly appreciated nowadays. Recently it was discovered that interaction between intestinal microbiota and unrhythmic circadian clock plays a key role in such a process. It involves relaying signals from microbiota through dendritic cells to group 3 innate lymphoid cells in the intestine and in the end impacting some of the key transcription factors of circadian clock. Breaking such a signal relay may prove to be an effective way reducing unrhythmic circadian clock-induced obesity. Here, we propose a hypothesis and design experiments to prove that suppressing one of the transcription factors, RUNX1, plays a key role in the homing of ILC3 cells to intestine. Such suppression is in response to a retinoic acid-RARα binding initiated pathway and results in the upregulation of gut-homing chemokine receptor CCR9 and downregulation of lymphoid tissue-homing receptor CCR7, which can then guide ILC3 cells to intestine. Therapies that can specifically sustain Runx1 expression in ILC3 cells may assist preventing the ever-escalating obesity problem in modern society.

A primary role for human central memory cells in tissue immunosurveillance

AbstractCentral memory T cells (TCM) patrol lymph nodes, providing central immunosurveillance against known pathogens, but have not been described as conducting primary tissue immunosurveillance. We analyzed the expression of tissue-homing addressins in human TCM vs effector memory T cells (TEM) from the same donors. In humans, the majority of human TCM were tropic for either skin or gut, and the overall tissue tropism of TCM was comparable to that of TEM. TCM were present in healthy, noninflamed human skin, lung, colon, and cervix, suggesting a role for TCM in the primary immunosurveillance of peripheral tissues. TCM also had potent effector functions; 80% of CD8+ TCM produced TC1/TC2/TC17/TC22 cytokines. TCM injected into human skin–grafted mice migrated into skin and induced inflammatory eruptions comparable to TEM-injected mice. In summary, human TCM express peripheral tissue-homing receptors at levels similar to their effector memory counterparts, are found in healthy human tissues, have impressive effector functions, and can act alone to induce skin inflammation in human engrafted mice. Our studies support a novel role for human TCM in primary immunosurveillance of peripheral tissues and highlight the important role of this long-lived cell type in tissue-based immune responses.

Prevention of acute graft-versus-host disease by anti-human OX40L monoclonal antibody

Abstract Graft-versus-host disease (GVHD) is one of the major hurdles for the success of solid organ and bone marrow transplantation. Numerous strategies to control alloreactive donor T cell responses have been used in the clinic with limited success. In this study, we investigated the effectiveness of anti-human OX40L monoclonal antibody (ahOX40L) in the prevention and treatment of acute GVHD (aGVHD) in a human xenogeneic model. NOD/SCID/γc−/−NOD.Cg-PrkdcscidIl2rgtm1Sug/Jic mice were transplanted with human PBMCs. Animals were treated with ahOX40L or control antibody either when human PBMCs were inoculated or at the onset of aGVHD. Clinical manifestations and immune profiles of human lymphocytes were monitored over time. ahOX40L treatment significantly alleviated disease severity and prolonged survival in both preventative and therapeutic models. Serological examination of circulating human PBMCs over the course of aGVHD revealed that ahOX40L treatment controls proliferation of CD45+CD3+ T cells, particularly CD8+ T cell expansion, resulting in an increased CD4+/CD8+ T cell ratio. In addition, ahOX40L treatment greatly reduced the infiltration of OX40-expressing CD3+ T cells in the target organs. In line with this, T cells in mice treated with ahOX40L decreased expression of tissue homing receptors. We further observed that ahOX40L treatment significantly down-regulated IL-21 and TNFα but increased IL-10 expression by T cells. Importantly, ahOX40L treatment was more effective in reducing aGVHD-associated mortality compared with neutralizing IL-21, TNFα or IL-21 plus TNFα. Altogether, our data support the clinical development of ahOX40L for the prevention and treatment of aGVHD.

Introduction: T Cell Trafficking in Inflammation and Immunity.

T cell migration across vascular endothelium is essential for T cell responses, as through the expression of specific tissue-homing receptors, these cells then access peripheral tissues, with the goal of eliminating invading pathogens and/or tumor cells. However, aberrant trafficking of T cells to peripheral tissues contributes to the development of most chronic inflammatory diseases. Very little is known about the mechanisms by which T cell trafficking is regulated during inflammation, and it is thus difficult to target this aspect of pathology for the development of new therapies. It is therefore important to understand the pathways involved in regulating the recruitment of immune cells.

ItpkB regulates CCR7 expression on dendritic cells prior to lymph node trafficking

Abstract Dendritic cells (DC) are fundamental in the initiation of the adaptive immune response. Following antigen uptake, tissue-resident DCs undergo maturation in preparation for their migration to lymph nodes where they present processed antigen to T cells. Down-regulation of tissue-homing receptors and upregulation of lymphoid-homing receptors, including CCR7 is required for dendritic cell entry into afferent lymphatic vessels. CCR7 binding to its ligands, CCL19 and CCL21, provides the appropriate directional cues for DCs to traffic to lymph nodes. Although both maturation and migration of DCs have been extensively studied, it still remains unclear what signaling pathways are responsible for inducing CCR7 expression. We found that DCs deficient in inositol-trisphosphate 3-kinase B (ItpkB) express higher levels of CCR7. ItpkB-deficient BMDCs migrate to draining lymph nodes more efficiently in both competitive and noncompetitive environments compared to their wild-type counterparts. We have previously shown that ItpkB deficiency leads to enhanced Akt activation in NK cells. Western blot analysis showed that ItpkB-deficiency in DCs also leads to increased basal and LPS-induced Akt1 activation. To determine whether hyper-Akt activity is sufficient to trigger enhanced lymph node homing, we expressed two forms of constitutively active Akt1, Myr-Akt1 and Akt1 T308E, S473D, in wildtype DCs. Akt1 hyperactivity was sufficient to promote CCR7 expression but did not affect DC maturation. Our findings suggest that ItpkB regulates CCR7 expression on dendritic cells as they prepare to traffic to draining lymph nodes for the purpose of primary T cell responses.

Resident memory T cells in mouse and human.

Recent researches are revealing the importance of a new subset of memory T cells called resident memory T cells (TRMs). Once they enter the tissues according to their tissue-homing receptors, TRMs do not go back to circulation and stay in the same tissues for a long time. These T cells are defined as expressing CD69 and/or CD103, and are known to show strong effector functions. It is considered that TRMs have an important role against infection in barrier tissues such as GI tract, skin, respiratory system and reproductive tract. Furthermore, recent reports indicate their roles in organ-specific chronic inflammatory disorders, autoimmune disorders and tumor immunology even in non-barrier tissues such as central nerve system, lymphatic tissue, liver, kidney, pancreas and joint. Here in this session, the author organized what have been known about TRM both in mouse and human, including the development, functional activities and relation of TRM to disease manifestation, for the detailed understanding of this fraction.

PD-L1/CD80 and PD-L1/PD-1 Signaling Reciprocally Regulate Alloreactive CD8+ T Cell Glycolysis, Proliferation, Apoptosis and Gvhd-Inducing Capacity

Graft versus host disease (GVHD) remains the major obstacle for widespread application of allogeneic hematopoietic cell transplantation (HCT), a curative therapy for hematological malignancies. We and others have reported that while sorted CD4+ T cells induce severe acute GVHD, the same numbers of CD8+ T cells induce no acute GVHD. CD8+ T cells can facilitate donor cell engraftment and mediate graft versus leukemia (GVL) effect in the absence of GVHD, but the mechanisms remain largely unknown. Programmed death-ligand 1 (PD-L1) interacts with both CD80 and PD-1. We have recently reported that simultaneous PD-L1/CD80 and PD-L1/PD-1 signaling augments activated alloreactive CD4+ T cell proliferation and apoptosis and ameliorates acute GVHD. However, the impact of this PD-L1-mediated signaling on alloreactive CD8+ T cells has not been investigated. In addition, T cell glycolytic metabolism has been recently reported to be able to regulate acute GVHD, and PD-L1/PD-1 signaling inhibits CD4+ T cell glycolytic flux, but how PD-L1/CD80 modulates T cell metabolism remains unstudied. In the current studies, we evaluated the role of PD-L1/CD80 and PD-L1/PD-1 signaling on alloreactive CD8+ T cell glycolysis, proliferation, apoptosis and GVHD-inducing capacity, using a MHC-mismatched murine HCT model of C57BL/6 (H-2b) donor to BABL/c recipient (H-2d). We have observed the following early (3-5 days) after HCT: 1) In wild-type (WT) recipients, PD-1-/- CD8+ T cells significantly upregulate expression of Glucose Transporter I (Glut1) and exhibit much higher rates of glycolytic flux; PD-1-/- CD8+ T cells also show markedly enhanced proliferation and reduced apoptosis as well as up-regulation of gut tissue homing and chemokine receptors (i.e. α4β7 and CCR9) and induce lethal GVHD, as compared to WT CD8+ T cells that induce little signs of GVHD. 2) In PD-L1-/- recipients, PD-1-/- CD8+ T cells reduce expression of Glut1 and no longer exhibit enhanced glycolytic flux or reduced apoptosis; PD-1-/- CD8+ T cells transplanted into PD-L1-/- recipients also induce little GVHD, similar to WT CD8+ T cells. 3) After injection of anti-PD-L1 mAb (clone 43H12) that specifically blocks PD-L1/CD80 interaction and preserves PD-L1/PD-1 interaction, WT CD8+ T cells in WT recipients show drastically reduced expansion, as compared to control recipients treated with rat-IgG. Blockade of PD-L1/CD80 interaction reduces phosphorylation of key elements in the TCR signaling cascade and CD28 co-stimulatory pathway including ZAP-70, AKT, mTOR and rpS6. Taken together, these studies indicate that 1) PD-L1/CD80 signaling alone augments alloreactive CD8+ T cell expansion and GVHD-inducing capacity; 2) PD-L1/CD80 and PD-L1/PD-1 signaling reciprocally regulate CD8+ T cell glycolysis, proliferation, and apoptosis as well as their GVHD-inducing capacity, and a balance of the two signaling pathways would be required to allow donor CD8+ T cells to facilitate engraftment and mediate GVL effect without causing GVHD. This work was supported by Institutional Funds of The Beckman Research Institute of City of Hope. DisclosuresNo relevant conflicts of interest to declare.

Correction: Peripheral Tissue Homing Receptors Enable T Cell Entry into Lymph Nodes and Affect the Anatomical Distribution of Memory Cells

Correction: Peripheral Tissue Homing Receptors Enable T Cell Entry into Lymph Nodes and Affect the Anatomical Distribution of Memory Cells

Bruton's tyrosine kinase (BTK) inhibitors in clinical trials.

BTK is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. Genetic BTK deletion causes B-cell immunodeficiency in humans and mice, making this kinase an attractive therapeutic target for B-cell disorders. The BTK inhibitor ibrutinib (PCI-32765, brand name: Imbruvica) demonstrated high clinical activity in B-cell malignancies, especially in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia (WM). Therefore, ibrutinib was granted a 'breakthrough therapy' designation for these indications and was recently approved for the treatment of relapsed MCL by the U.S. Food and Drug Administration. Other BTK inhibitors in earlier clinical development include CC-292 (AVL-292), and ONO-4059. In CLL and MCL, ibrutinib characteristically induces redistribution of malignant B cells from tissue sites into the peripheral blood, along with rapid resolution of enlarged lymph nodes and a surge in lymphocytosis. With continuous ibrutinib therapy, growth- and survival-inhibitory activities of ibrutinib result in the normalization of lymphocyte counts and remissions in a majority of patients. This review discusses the clinical advances with BTK inhibitor therapy, as well as its pathophysiological basis, and outlines perspectives for future use of BTK inhibitors.

Correction: Peripheral Tissue Homing Receptors Enable T Cell Entry into Lymph Nodes and Affect the Anatomical Distribution of Memory Cells

Correction: Peripheral Tissue Homing Receptors Enable T Cell Entry into Lymph Nodes and Affect the Anatomical Distribution of Memory Cells

Peripheral Tissue Homing Receptors Enable T Cell Entry into Lymph Nodes and Affect the Anatomical Distribution of Memory Cells

Peripheral tissue homing receptors enable T cells to access inflamed nonlymphoid tissues. In this study, we show that two such molecules, E-selectin ligand and α4β1 integrin, enable activated and memory T cells to enter lymph nodes (LN) as well. This affects the quantitative and qualitative distribution of these cells among regional LN beds. CD8 memory T cells in LN that express these molecules were mostly CD62L(lo) and would normally be classified as effector memory cells. However, similar to central memory cells, they expanded upon Ag re-encounter. This led to differences in the magnitude of the recall response that depended on the route of immunization. These novel cells share properties of both central and effector memory cells and reside in LN based on previously undescribed mechanisms of entry.

Peripheral Tissue Homing Receptor Control of Naïve, Effector, and Memory CD8 T Cell Localization in Lymphoid and Non-Lymphoid Tissues

T cell activation induces homing receptors that bind ligands on peripheral tissue vasculature, programing movement to sites of infection and injury. There are three major types of CD8 effector T cells based on homing receptor expression, which arise in distinct lymphoid organs. Recent publications indicate that naïve, effector, and memory T cell migration is more complex than once thought; while many effectors enter peripheral tissues, some re-enter lymph nodes (LN), and contain central memory precursors. LN re-entry can depend on CD62L or peripheral tissue homing receptors. Memory T cells in LN tend to express the same homing receptors as their forebears, but often are CD62Lneg. Homing receptors also control CD8 T cell tumor entry. Tumor vasculature has low levels of many peripheral tissue homing receptor ligands, but portions of it resemble high endothelial venules (HEV), enabling naïve T cell entry, activation, and subsequent effector activity. This vasculature is associated with positive prognoses in humans, suggesting it may sustain ongoing anti-tumor responses. These findings reveal new roles for homing receptors expressed by naïve, effector, and memory CD8 T cells in controlling entry into lymphoid and non-lymphoid tissues.

Regulatory T Cells Inhibit CD8+ T-Cell Tissue Invasion in Human Skin Graft-Versus-Host Reactions

Regulatory T cells (Tregs) effectively ameliorate graft-versus-host disease (GVHD). The mechanisms underlying Treg therapeutic effect on GVHD are not fully elucidated. This study investigates whether Treg prevention of GVH tissue damage is associated with blocking CD8 effector T-cell tissue invasion, a question not yet addressed in humans. Tissue-infiltrating T cells and histopathology scores were detected using an in vitro human GVHD skin explant model, together with immunohistochemistry, cytometric bead array, functional adhesion and migration assays, flow cytometry, and quantitative real-time polymerase chain reaction. Treg intervention during priming significantly decreased effector T-cell infiltration into target tissue (P<0.01) resulting in a striking reduction in the histopathology score of tissue injury (P<0.0001). These results were coupled with reduced CXCR3 and cutaneous lymphocyte antigen expression by effector T cells, together with decreased CXCL10 and CXCL11 expression in target tissue. Treg intervention also impaired the functional interaction of CXCR3 and cutaneous lymphocyte antigen with their specific ligands (P<0.01) and suppressed the secretion of CXCL9, CXCL10, and interferon-γ (P<0.01, P<0.05, and P<0.001, respectively). Late addition of Tregs into the effector phase abolished their ability to suppress effector T-cell tissue invasion, resulting in a total loss of their ability to ameliorate GVH tissue damage. Preventing effector T-cell tissue invasion is a critical mechanistic event leading to Treg attenuation of GVH tissue damage. This therapeutic effect is associated with a failure of CD8 T cells to increase tissue homing receptors after allo-stimulation, together with a breakdown of interferon-γ-induced chemoattractant expression in the target tissue.