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    GPR18 is required for a normal CD8αα intestinal intraepithelial lymphocyte compartment. Wang Xiaoming,Sumida Hayakazu,Cyster Jason G The Journal of experimental medicine Intraepithelial lymphocytes (IELs) play an important role in maintaining the physiology of the small intestine. The majority of mouse IELs express CD8αα and are either γδ or αβ T cells. Although the development and homing of CD8αα IELs have been studied in some detail, the factors controlling their homeostasis and positioning are incompletely understood. Here we demonstrate that G protein-coupled receptor 18 (GPR18) is abundantly expressed in CD8αα IELs and that mice lacking this orphan receptor have reduced numbers of γδT IELs. Mixed bone marrow chimera experiments reveal a markedly reduced contribution of GPR18-deficient cells to the CD8αα IEL compartment and a reduction in the CD8αβ T cell subset. These defects could be rescued by transduction with a GPR18-expressing retrovirus. The GPR18-deficient γδT IELs that remained in mixed chimeras had elevated Thy1, and there were less granzyme B(+) and Vγ7(+) cells, indicating a greater reduction in effector-type cells. Flow cytometric analysis indicated GPR18 deficiency more strongly affected the CD8αα cells in the intraepithelial compared with the adjacent lamina propria compartment. These findings establish a requirement for GPR18 in CD8αα and CD8αβ IELs, and we suggest the receptor has a role in augmenting the accumulation of CD8 T cells in the intraepithelial versus lamina propria compartment. 10.1084/jem.20140646
    β2 Integrins differentially regulate γδ T cell subset thymic development and peripheral maintenance. McIntyre Claire L,Monin Leticia,Rop Jesse C,Otto Thomas D,Goodyear Carl S,Hayday Adrian C,Morrison Vicky L Proceedings of the National Academy of Sciences of the United States of America The γδ T cells reside predominantly at barrier sites and play essential roles in immune protection against infection and cancer. Despite recent advances in the development of γδ T cell immunotherapy, our understanding of the basic biology of these cells, including how their numbers are regulated in vivo, remains poor. This is particularly true for tissue-resident γδ T cells. We have identified the β family of integrins as regulators of γδ T cells. β-integrin-deficient mice displayed a striking increase in numbers of IL-17-producing Vγ6Vδ1 γδ T cells in the lungs, uterus, and circulation. Thymic development of this population was normal. However, single-cell RNA sequencing revealed the enrichment of genes associated with T cell survival and proliferation specifically in β-integrin-deficient IL-17 cells compared to their wild-type counterparts. Indeed, β-integrin-deficient Vγ6 cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in β-integrin-deficient tissues. Furthermore, our data revealed an unexpected role for β integrins in promoting the thymic development of the IFNγ-producing CD27 Vγ4 γδ T cell subset. Together, our data reveal that β integrins are important regulators of γδ T cell homeostasis, inhibiting the survival of IL-17-producing Vγ6Vδ1 cells and promoting the thymic development of the IFNγ-producing Vγ4 subset. Our study introduces unprecedented mechanisms of control for γδ T cell subsets. 10.1073/pnas.1921930117
    Intraepithelial lymphocytes. Hoytema van Konijnenburg David P,Mucida Daniel Current biology : CB Hoytema van Konijnenburg and Mucida discuss development and function of intraepithelial lymphocytes, which are found within the epithelial layer of mucosal and barrier tissues. 10.1016/j.cub.2017.05.073
    Separate lineages of T cells expressing the alpha beta and gamma delta receptors. Winoto A,Baltimore D Nature The T-cell antigen receptor is a heterodimer molecule composed of either alpha beta or gamma delta chains. The alpha beta receptor molecules are expressed mainly in CD4+ CD8- and CD4- CD8+ T cells (helper and killer T cells respectively), whereas the gamma delta receptor molecules are expressed mainly in CD4- CD8- T cells. CD4+CD8- and CD4-CD8+ T cells arise from a class of CD4-CD8- T cells during thymus development, raising the question of whether cells rearranging their gamma delta receptors later give rise to alpha beta T cells by further rearrangements of their receptor genes, or whether rearrangements and expression of the receptor genes occur in separate lineages. The delta-chain gene is located between the V alpha (variable) and J alpha (joining) gene segments, and when the rearrangements allowing alpha- and beta-receptors occur, the DNA between these segments is deleted as small circles which can be isolated from developing thymocytes. The rearrangement status of the delta-chain gene in the alpha-circles can therefore be investigated to see whether alpha-chain and delta-chain expression occur in parallel lineages or sequentially within a lineage. We find that the delta-chain gene in the T-cell receptor alpha-circles has a germline configuration, indicating that alpha beta and gamma delta T cells are distinct lineages. 10.1038/338430a0
    The immunobiology of T cells with invariant gamma delta antigen receptors. Allison J P,Havran W L Annual review of immunology T cells bearing specific gamma delta TCR are the major lymphoid population in certain epithelial tissues. There are striking differences between these and peripheral T cells. The epithelial gamma delta T cells exhibit highly restricted V gene use, preferential pairing of TCR chains, and lack of diversity at the junctions creating populations of cells with virtually identical TCR in particular epithelia. Generation of certain epithelial gamma delta populations appears to be restricted to a discrete stage early in development. The restricted localization and expression of invariant antigen receptors may equip the epithelial gamma delta T cells to perform specialized functions which differ from those of circulating alpha beta and gamma delta TCR+ cells. This review provides a summary of the characterization of gamma delta T cells found in epithelial tissues and speculates on the in vivo role of these cells. 10.1146/annurev.iy.09.040191.003335
    Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells. Eberl Gérard,Littman Dan R Science (New York, N.Y.) Intestinal intraepithelial T lymphocytes (IELs) are likely to play a key role in host mucosal immunity and, unlike other T cells, have been proposed to differentiate from local precursors rather than from thymocytes. We show here that IELs expressing the alphabeta T cell receptor are derived from precursors that express RORgammat, an orphan nuclear hormone receptor detected only in immature CD4+CD8+ thymocytes, fetal lymphoid tissue-inducer (LTi) cells, and LTi-like cells in cryptopatches within the adult intestinal lamina propria. Using cell fate mapping, we found that all intestinal alphabeta T cells are progeny of CD4+CD8+ thymocytes, indicating that the adult intestine is not a significant site for alphabeta T cell development. Our results suggest that intestinal RORgammat+ cells are local organizers of mucosal lymphoid tissue. 10.1126/science.1096472
    Mutations in T-cell antigen receptor genes alpha and beta block thymocyte development at different stages. Mombaerts P,Clarke A R,Rudnicki M A,Iacomini J,Itohara S,Lafaille J J,Wang L,Ichikawa Y,Jaenisch R,Hooper M L Nature Analysis of mice carrying mutant T-cell antigen receptor (TCR) genes indicates that TCR-beta gene rearrangement or expression is critical for the differentiation of CD4-CD8- thymocytes to CD4+CD8+ thymocytes, as well as for the expansion of the pool of CD4+CD8+ cells. TCR-alpha is irrelevant in these developmental processes. The development of gamma delta T cells does not depend on either TCR-alpha or TCR-beta. 10.1038/360225a0
    Distinct structure and signaling potential of the gamma delta TCR complex. Hayes Sandra M,Love Paul E Immunity Alpha beta and gamma delta T cells are distinguished by the clonotypic subunits contained within their TCRs. Although the alpha beta TCR has been well characterized, much less is known about the gamma delta TCR. Here, we report that, unlike alpha beta T CRs, most gamma delta TCRs expressed on ex vivo gamma delta T cells lack CD3 delta. Despite this structural difference, signal transduction by the gamma delta TCR is superior to that of the alpha beta TCR, as measured by its ability to induce calcium mobilization, ERK activation, and cellular proliferation. Additionally, the TCR complexes expressed on primary gamma delta T cells contain only zeta zeta homodimers; however, following activation and expansion, Fc epsilon R1 gamma is expressed and is included in the gamma delta TCR complex. These results reveal fundamental differences in the primary structure and signaling potential of the alpha beta- and gamma delta TCR complexes.
    Self-tolerance to transgenic gamma delta T cells by intrathymic inactivation. Bonneville M,Ishida I,Itohara S,Verbeek S,Berns A,Kanagawa O,Haas W,Tonegawa S Nature During their intrathymic differentiation, T lymphocytes expressing alpha beta T-cell receptors (TCR) are negatively and positively selected. This selection contributes to the establishment of self-tolerance and ensures that mature CD4+ and CD8+ cell populations are restricted by the self major histocompatibility complex. Little is known, however, about gamma delta T-cell development. To investigate whether selection operates in the establishment of the gamma delta T-cell class, we have generated transgenic mice using gamma- and delta-transgenes encoding a TCR that is specific for a product of a gene in the TL-region of the TLb haplotype. Similar numbers of thymocytes expressing the transgenic TCR were generated in mice of TLb and TLd haplotypes. But gamma delta thymocytes from TLb and TLd transgenic mice differed in cell size, TCR density and in their capacity to respond to TLb stimulator cells or interleukin-2 (IL-2). In contrast to gamma delta T cells from TLd transgenic mice, gamma delta T cells from TLb transgenic mice did not produce IL-2 and did not proliferate in response to TLb stimulator cells, but they did proliferate in the presence of exogenous IL-2. These results indicate that functional inactivation of self-antigen-specific T cells could contribute to the establishment of self-tolerance to thymic determinants. 10.1038/344163a0
    Selective outgrowth of CD45RO+ V gamma 9+/V delta 2+ T-cell receptor gamma/delta T cells early after bone marrow transplantation. van der Harst D,Brand A,van Luxemburg-Heijs S A,Kooij-Winkelaar Y M,Zwaan F E,Koning F Blood Before and after bone marrow transplantation (BMT) for hematologic malignancies, peripheral blood mononuclear cells from 10 patients were obtained. The relative and absolute numbers of CD3+ T-cell receptor gamma delta+ (TCR gamma delta+) cells, as defined by the reaction of monoclonal antibodies (MoAbs) directed against CD3 and the TCR gamma delta (anti-TCR gamma delta-1), were determined. Before transplantation, eight of nine patients tested had less than 10% CD3+TCR gamma delta+ cells. Consistent increased numbers of gamma delta cells up to eightfold the pretransplant level can be seen in four of nine patients tested within the first 4 months after BMT. The large majority of early posttransplant gamma delta and alpha beta T cells express the CD45RO antigen, which is usually expressed on "memory" cells only. The V-region usage of the TCR gamma delta+ T cells was analyzed using fresh mononuclear cells and MoAbs against known V gamma and V delta regions. For more detailed analysis, CD3+TCR gamma delta+ cells were sorted and cultured in bulk and cloned. Using fresh cells and bulk cultures, mainly V gamma 9+V delta 1-V delta 2+ cells were found during engraftment. Only after 6 weeks post-BMT, V gamma 9-V delta 1+V delta 2- cells appear. Analysis of the V gamma and V delta usage at the clonal level confirmed the observation that early after BMT only V gamma 9+V delta 2+ cells are present, whereas gamma delta T-cell clones expressing other gamma delta TCR phenotypes can only be detected 4 to 6 weeks post-BMT. The predominance of V gamma 9+ cells during early engraftment could be explained by several mechanisms: (A) sequential rearrangements during T-cell development, leading to an early wave of V gamma 9+ cells, or (B) selective outgrowth of preexisting V gamma 9+V delta 2+CD45RO+ TCR gamma delta cells in the bone marrow graft, possibly as a result of antigen driven expansion due to exposure to environmental antigens.
    Crucial role of the pre-T-cell receptor alpha gene in development of alpha beta but not gamma delta T cells. Fehling H J,Krotkova A,Saint-Ruf C,von Boehmer H Nature In T-cell precursors, the T-cell-receptor beta chain is expressed before the T-cell-receptor alpha chain and is sufficient to advance T-cell development in the absence of T-cell receptor alpha chains. In immature T cells, the T-cell-receptor beta protein can form disulphide-linked heterodimers with the pre-T-cell-receptor alpha chain and associate with signal-transducing CD3 molecules. The recently cloned pre-T-cell-receptor alpha gene encodes a transmembrane protein that is expressed in immature but not mature T cells. Here we show that alpha beta, but not gamma delta, cell development is severely hampered in pre-T-cell-receptor alpha-gene-deficient mice, which establishes a crucial role for the pre-T-cell receptor in early thymocyte development. 10.1038/375795a0
    Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Cao X,Shores E W,Hu-Li J,Anver M R,Kelsall B L,Russell S M,Drago J,Noguchi M,Grinberg A,Bloom E T Immunity The common gamma chain (gamma c) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors is defective in humans with XSCID. Mice lacking gamma c expression had hypoplastic thymuses; the thymocytes responded to gamma c-independent mitogens, but not gamma c-dependent stimuli. Splenic T cells were diminished at 3 weeks of age, but CD4+ T cells markedly increased by 4 weeks. B cells were greatly diminished in contrast with the situation in XSCID. NK cells, gamma delta intestinal intraepithelial lymphocytes, dendritic epidermal T cells, peripheral lymph nodes, and gut-associated lymphoid tissue were absent. These findings underscore the importance of gamma c in lymphoid development. Moreover, differences in humans and mice lacking gamma c expression indicate species-specific differences in the roles of gamma c-dependent cytokines or in the existence of redundant pathways. These mice provide an important model for studying the pathophysiology provide an important model for studying the pathophysiology of and gene therapy for human XSCID.
    Adhesion molecules expressed on homing lymphocytes in model intestinal epithelia. Shibahara T,Si-Tahar M,Shaw S K,Madara J L Gastroenterology BACKGROUND & AIMS:The development of intestinal intraepithelial lymphocytes (IELs) requires the movement of lymphocytes into the epithelial compartment (i.e., IEL homing). The rules governing and the biologic consequences of IEL homing are poorly understood. The aims of this study were to examine the adhesion molecules involved in IEL homing and the phenotypic alteration of lymphocytes as a consequence of homing. METHODS:We previously developed an in vitro IEL homing model consisting of human IEL cell lines and a polarized monolayer of human intestinal epithelial T84 cells. Homing capacity of lymphocytes was assessed by measuring their migration into epithelial monolayers, and phenotypic analysis was performed by flow cytometry. RESULTS:In this model, approximately 30% of lymphocytes moved into the epithelial monolayer, regardless of the lymphocyte concentration. Flow cytometric screening of adhesion molecules revealed that homed lymphocytes expressed high levels of integrin alphaXbeta2 and alphaEbeta7 and low levels of alpha4beta7 compared with non-homed lymphocytes. In addition, subpopulations sorted as alphaXbeta2(high) or alphaEbeta7(high) independently showed greater homing capacities. After homing, alphaEbeta7 and intercellular adhesion molecule 1 (ICAM-1) on homed lymphocytes were significantly up-regulated, which was consistent with their high expression observed on freshly isolated human IELs. The up-regulation of alphaEbeta7 (but not ICAM-1) was completely dependent on epithelial-derived transforming growth factor beta1 (TGF-beta1). The expression of alphaXbeta2 was observed on a small population of freshly isolated human IELs, and was markedly induced by stimulation. Also, epithelial-derived TGF-beta1 down-regulated the alphaXbeta2 expression (an event likely to occur after homing). CONCLUSIONS:Our findings indicate a relationship between IEL alphaXbeta2 and alphaEbeta7 expression and homing into intestinal epithelia. We also show that phenotypic alteration of IELs is induced by close interaction with intestinal epithelia as a consequence of homing. 10.1016/s0016-5085(00)70211-3
    T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells. Park Sung-Gyoo,Mathur Ramkumar,Long Meixiao,Hosh Namiko,Hao Liming,Hayden Matthew S,Ghosh Sankar Immunity Immune tolerance against enteric commensal bacteria is important for preventing intestinal inflammation. Deletion of phosphoinositide-dependent protein kinase 1 (Pdk1) in T cells via Cd4-Cre induced chronic inflammation of the intestine despite the importance of PDK1 in T cell activation. Analysis of colonic intraepithelial lymphocytes of PDK1-deficient mice revealed markedly increased CD8α(+) T cell receptor (TCR)γδ(+) T cells, including an interleukin-17 (IL-17)-expressing population. TCRγδ(+) T cells were responsible for the inflammatory colitis as shown by the fact that deletion of Tcrd abolished spontaneous colitis in the PDK1-deficient mice. This dysregulation of intestinal TCRγδ(+) T cells was attributable to a reduction in the number and functional capacity of PDK1-deficient T regulatory (Treg) cells. Adoptive transfer of wild-type Treg cells abrogated the spontaneous activation and proliferation of intestinal TCRγδ(+) T cells observed in PDK1-deficient mice and prevented the development of colitis. Therefore, suppression of intestinal TCRγδ(+) T cells by Treg cells maintains enteric immune tolerance. 10.1016/j.immuni.2010.10.014
    Heat-stable antigen may be an early marker of extrathymic murine intestinal intraepithelial lymphocytes. Stickney D G,Wang J,Hamad M,Klein J R Blood Using a system of bone marrow (BM) hematopoietic repopulation of irradiated euthymic and athymic mice, we have examined the early stages of extrathymic T-cell development within the murine small intestine epithelium. During a period of active extrathymic T-cell development, two distinct populations of intraepithelial lymphocytes (IEL) were present. One consisted of CD3+ lymphocytes with phenotypic properties of mature IEL. The other population consisted of a transient IEL subset that increased in abundance between days 5 and 14 post-BM transfer, and then declined. The majority of transient IEL in both types of mice expressed the heat-stable antigen, of which some cells coexpressed CD3 but were void of other markers common to mature T cells. Studies using freshly extracted IEL from normal nonirradiated mice found that approximately 3% to 5% of the IEL had phenotypic properties similar to the transient IEL observed during repopulation of radiation chimeras, indicating that such IEL are present within the gut epithelium of normal, nonirradiated mice. Identification of this IEL subset should greatly facilitate studies of extrathymic IEL development.
    T-bet orchestrates CD8αα IEL differentiation. Kwong Brandon,Lazarevic Vanja Immunity Very little is known about the transcription factor network that regulates the development of intestinal intraepithelial lymphocytes (IELs). In this issue of Immunity, Klose et al. (2014b) and Reis et al. (2014) demonstrate an essential role for T-bet in regulating the CD8αα IEL differentiation program. 10.1016/j.immuni.2014.08.003
    Development of intraepithelial T lymphocytes in the intestine of irradiated SCID mice by adult liver hematopoietic stem cells from normal mice. Yamagiwa S,Seki S,Shirai K,Yoshida Y,Miyaji C,Watanabe H,Abo T Journal of hepatology BACKGROUND/AIMS:We recently reported the adult mouse liver to contain c-kit+ stem cells that can give rise to multilineage leukocytes. This study was designed to determine whether or not adult mouse liver stem cells can generate intraepithelial T cells in the intestine as well as to examine the possibility that adult liver c-kit+ stem cells originate from the fetal liver. METHODS:Adult liver mononuclear cells, bone marrow (BM) cells, liver c-kit+ cells or bone BM c-kit+ cells of BALB/c mice were i.v. transferred into 4 Gy irradiated CB17/-SCID mice. In other experiments, fetal liver cells from Ly5.1 C57BL/6 mice and T cell depleted adult BM cells from Ly5.2 C57BL/6 mice were simultaneously transferred into irradiated C57BL/6 SCID mice (Ly5.2). At 1 to 8 weeks after cell transfer, the SCID mice were examined. RESULTS:Not only BM cells and BM c-kit+ cells but also liver mononuclear cells and liver c-kit+ cells reconstituted gamma delta T cells, CD4+ CD8+ double-positive T cells and CD8 alpha+beta- T cells of intestinal intraepithelial lymphocytes of SCID mice. Injection of a mixture of fetal liver cells from Ly5.1 C57BL/6 mice and adult BM cells from Ly5.2 C57BL/6 mice into Ly5.2 C57BL/6 SCID mice induced both Ly5.1 and Ly5.2 T cells, while also generating c-kit+ cells of both Ly5.1 and Ly5.2 origins in the liver. CONCLUSIONS:Adult mouse liver stem cells were able to generate intestinal intraepithelial T cells of the SCID mice, and it is thus suggested that some adult liver stem cells may indeed be derived from the fetal liver.
    Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Di Sabatino A,Ciccocioppo R,Cupelli F,Cinque B,Millimaggi D,Clarkson M M,Paulli M,Cifone M G,Corazza G R Gut BACKGROUND AND AIMS:Epithelium derived interleukin (IL)-15 signalling via IL-15Ralpha is critical for the development, activation, and survival of intraepithelial lymphocytes (IEL). We aimed to better understand the IL-15 driven effects on IEL underlying mucosal damage and lymphomagenesis in coeliac disease (CD). METHODS:Enterocytes, IEL, and lamina propria mononuclear cells (LPMC) were isolated from 46 patients with uncomplicated CD (25 untreated and 21 treated) and 22 controls. IL-15 and IL-15Ralpha expression were determined by immunoblotting. Secretion of IL-15, interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), and granzyme B into cell culture supernatants was assessed by ELISA. The ability of IL-15 to regulate IEL proliferation, perforin/granzyme dependent cytotoxicity, and apoptosis was tested by adding different combinations of IL-15, IL-15 blocking antibody, or chloroquine to IEL cultured alone or with Caco-2 cells as target. IL-15 mucosal levels were also determined by ELISA in five patients with complicated CD (two ulcerative jejunoileites, one refractory sprue, and two enteropathy associated T cell lymphomas) tested for T cell receptor gamma chain clonality. RESULTS:IL-15 was overexpressed in untreated CD enterocytes and LPMC, and in the mucosa of complicated CD patients and uncomplicated untreated CD patients, where its levels correlated with the degree of mucosal damage. Enterocytes from untreated, but not treated, CD patients and controls secreted IL-15. Untreated CD IEL, characterised by higher IL-15Ralpha expression, showed increased proliferation, production of IFN-gamma and TNF-alpha, and perforin/granzyme dependent cytotoxicity, and a decreased propensity to apoptosis in response to IL-15. CONCLUSIONS:Our findings suggest that IL-15 plays a crucial role in the generation of epithelial damage in active CD. Its promotion of IEL survival in CD may predispose to the emergence of T cell clonal proliferations. Blocking IL-15, by suppressing uncontrolled IEL activation and survival, has the potential to provide new therapeutic tools to prevent tissue damage and lymphomagenesis in CD. 10.1136/gut.2005.068684
    Activation and peripheral expansion of murine T-cell receptor gamma delta intraepithelial lymphocytes. Guehler S R,Bluestone J A,Barrett T A Gastroenterology BACKGROUND & AIMS:The intestinal epithelial compartment is populated by CD8(+) alpha beta and gamma delta intraepithelial lymphocytes (IELs), which monitor the integrity of the epithelial barrier. alpha beta IELs are activated by peptide antigens presented by class I major histocompatibility complex (MHC) molecules, but it is unclear how gamma delta IELs are activated. METHODS:G8 T-cell receptor (TCR) gamma delta transgenic (Tg) mice (specific for the class I MHC alloantigen, T22/10(b)) were crossed to class I MHC-deficient beta2-microglobulin-knockout (beta2m degrees) mice, and Tg+ IELs were examined for relative yields and surface and functional phenotype. RESULTS:Evidence for class I MHC-induced activation of Tg+ IELs was supported by the detection of 4-fold greater numbers of Tg+ IELs in G8 x beta2m+ mice that proliferated at 15-fold higher levels than IELs from G8 x beta2m degrees mice. However, expression of CD69, production of cytokine (interleukin 2 and interferon gamma), and detection of cytolytic function for IELs in G8 x beta2m degrees mice suggested that class I MHC was not required for gamma delta IEL development or maturation. CONCLUSIONS:These results suggest that CD8(+) TCR gamma delta IELs do not require class I MHC for development but support the notion that antigens presented by class I MHC molecules are involved in the peripheral expansion and differentiation of this subset. 10.1016/s0016-5085(99)70129-0
    Unconventional intraepithelial gut T cells: the TCR says it all. Kurd Nadia,Robey Ellen A Immunity The intestinal epithelium harbors a large number of T cells, including TCRαβ cells that lack expression of CD4 and CD8αβ coreceptors. In this issue of Immunity, Mayans et al. (2014) and McDonald et al. (2014) shed light on the specificity and development of this enigmatic T cell population. 10.1016/j.immuni.2014.08.004
    The ARNT-STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ⁺CD8αα⁺ cells. Nakajima Kohei,Maekawa Yoichi,Kataoka Keiko,Ishifune Chieko,Nishida Jun,Arimochi Hideki,Kitamura Akiko,Yoshimoto Takayuki,Tomita Shuhei,Nagahiro Shinji,Yasutomo Koji Nature communications Intestinal intraepithelial T cells contribute to the regulation of inflammatory responses in the intestine; however, the molecular basis for their development and maintenance is unknown. The aryl hydrocarbon receptor complexes with the aryl hydrocarbon receptor nuclear translocator (ARNT) and senses environmental factors, including gut microbiota. Here, we identify ARNT as a critical regulator of the differentiation of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells. Mice deficient in either ARNT or aryl hydrocarbon receptor show a greater than- eight-fold reduction in the number of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells. The number of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells is increased by treatment with an aryl hydrocarbon receptor agonist in germ-free mice and is decreased by antibiotic treatment. The Arnt-deficient precursors of TCRαβ(+)CD8αα(+) intestinal intraepithelial T cells express low amounts of STAT3 and fail to differentiate towards the TCRαβ(+)CD8αα(+) cell fate after IL-15 stimulation, a deficiency that is overcome by overexpression of Stat3. These data demonstrate that the ARNT-STAT3 axis is a critical regulator of TCRαβ(+)CD8αα(+) intestinal intraepithelial T-cell development and differentiation. 10.1038/ncomms3112
    HEB is required for the specification of fetal IL-17-producing γδ T cells. In Tracy S H,Trotman-Grant Ashton,Fahl Shawn,Chen Edward L Y,Zarin Payam,Moore Amanda J,Wiest David L,Zúñiga-Pflücker Juan Carlos,Anderson Michele K Nature communications IL-17-producing γδ T (γδT17) cells are critical components of the innate immune system. However, the gene networks that control their development are unclear. Here we show that HEB (HeLa E-box binding protein, encoded by Tcf12) is required for the generation of a newly defined subset of fetal-derived CD73 γδT17 cells. HEB is required in immature CD24CD73 γδ T cells for the expression of Sox4, Sox13, and Rorc, and these genes are repressed by acute expression of the HEB antagonist Id3. HEB-deficiency also affects mature CD73 γδ T cells, which are defective in RORγt expression and IL-17 production. Additionally, the fetal TCRγ chain repertoire is altered, and peripheral Vγ4 γδ T cells are mostly restricted to the IFNγ-producing phenotype in HEB-deficient mice. Therefore, our work identifies HEB-dependent pathways for the development of CD73 and CD73 γδT17 cells, and provides mechanistic evidence for control of the γδT17 gene network by HEB. 10.1038/s41467-017-02225-5
    Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. Wurbel M A,Malissen M,Guy-Grand D,Meffre E,Nussenzweig M C,Richelme M,Carrier A,Malissen B Blood CC chemokine receptor (CCR) 9, the receptor for the CC-chemokine CCL25/thymus-expressed chemokine (TECK), is mainly expressed by thymocytes and by intraepithelial (IEL) and lamina propria lymphocytes of the small intestine. To study the biologic role of CCR9, a mouse strain was generated in which the CCR9 gene was deleted. In spite of the high level of CCR9 found in double- and single-positive thymocytes and of the expression of its corresponding ligand on thymic stromal cells, CCR9 deletion had no major effect on intrathymic T-cell development. It was noted that there was only a one-day lag in the appearance of double-positive cells during fetal ontogeny in CCR9(-/-) thymi. When tested in chemotaxis assay, thymocytes isolated from CCR9(-/-) mice failed to respond to TECK/CCL25. Taken together, these results suggest that in thymocytes, CCR9 is the only physiologic receptor for TECK/CCL25, and that it is dispensable for proper T-cell development. Bone marrow pre-pro-B cells migrate in response to TECK/CCL25, but more mature B cells do not. Consistent with this observation, it was shown that there are fewer pre-pro-B cells in CCR9(-/-) mice than in wild-type mice. However, this diminution does not appear to have a detectable effect on the generation of a normal complement of mature B cells. Finally, it was shown that in the small intestine of CCR9-deficient mice, the intraepithelial T-cell-to-epithelial cell ratio is decreased, an observation that can be accounted for by a marked diminution of the T-cell receptor gammadelta(+) compartment. 10.1182/blood.v98.9.2626
    Interleukin 17-producing γδT cells promote hepatic regeneration in mice. Rao Raghavendra,Graffeo Christopher S,Gulati Rishabh,Jamal Mohsin,Narayan Suchithra,Zambirinis Constantinos P,Barilla Rocky,Deutsch Michael,Greco Stephanie H,Ochi Atsuo,Tomkötter Lena,Blobstein Reuven,Avanzi Antonina,Tippens Daniel M,Gelbstein Yisroel,Van Heerden Eliza,Miller George Gastroenterology BACKGROUND & AIMS:Subsets of leukocytes synergize with regenerative growth factors to promote hepatic regeneration. γδT cells are early responders to inflammation-induced injury in a number of contexts. We investigated the role of γδT cells in hepatic regeneration using mice with disruptions in Tcrd (encodes the T-cell receptor δ chain) and Clec7a (encodes C-type lectin domain family 7 member a, also known as DECTIN1). METHODS:We performed partial hepatectomies on wild-type C57BL/6, CD45.1, Tcrd(-/-), or Clec7a(-/-) mice. Cells were isolated from livers of patients and mice via mechanical and enzymatic digestion. γδT cells were purified by fluorescence-activated cell sorting. RESULTS:In mice, partial hepatectomy up-regulated expression of CCL20 and ligands of Dectin-1, which was associated with recruitment and activation of γδT cells and their increased production of interleukin (IL)-17 family cytokines. Recruited γδT cells induced production of IL-6 by antigen-presenting cells and suppressed expression of interferon gamma by natural killer T cells, promoting hepatocyte proliferation. Absence of IL-17-producing γδT cells or deletion of Dectin-1 prevented development of regenerative phenotypes in subsets of innate immune cells. This slowed liver regeneration and was associated with reduced expression of regenerative growth factors and cell cycle regulators. Conversely, exogenous administration of IL-17 family cytokines or Dectin-1 ligands promoted regeneration. More broadly, we found that γδT cells are required for inflammatory responses mediated by IL-17 and Dectin-1. CONCLUSIONS:γδT cells regulate hepatic regeneration by producing IL-22 and IL-17, which have direct mitogenic effects on hepatocytes and promote a regenerative phenotype in hepatic leukocytes, respectively. Dectin-1 ligation is required for γδT cells to promote hepatic regeneration. 10.1053/j.gastro.2014.04.042
    The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner. Li Fenglei,Hao Xiaolei,Chen Yongyan,Bai Li,Gao Xiang,Lian Zhexiong,Wei Haiming,Sun Rui,Tian Zhigang Nature communications The microbiota control regional immunity using mechanisms such as inducing IL-17A-producing γδ T (γδT-17) cells in various tissues. However, little is known regarding hepatic γδT cells that are constantly stimulated by gut commensal microbes. Here we show hepatic γδT cells are liver-resident cells and predominant producers of IL-17A. The microbiota sustain hepatic γδT-17 cell homeostasis, including activation, survival and proliferation. The global commensal quantity affects the number of liver-resident γδT-17 cells; indeed, E. coli alone can generate γδT-17 cells in a dose-dependent manner. Liver-resident γδT-17 cell homeostasis depends on hepatocyte-expressed CD1d, that present lipid antigen, but not Toll-like receptors or IL-1/IL-23 receptor signalling. Supplementing mice in vivo or loading hepatocytes in vitro with exogenous commensal lipid antigens augments the hepatic γδT-17 cell number. Moreover, the microbiota accelerate nonalcoholic fatty liver disease through hepatic γδT-17 cells. Thus, our work describes a unique liver-resident γδT-17 cell subset maintained by gut commensal microbes through CD1d/lipid antigens. 10.1038/ncomms13839
    Evidence that tissue resident human enthesis γδT-cells can produce IL-17A independently of IL-23R transcript expression. Cuthbert Richard James,Watad Abdulla,Fragkakis Evangelos M,Dunsmuir Robert,Loughenbury Peter,Khan Almas,Millner Peter A,Davison Adam,Marzo-Ortega Helena,Newton Darren,Bridgewood Charlie,McGonagle Dennis G Annals of the rheumatic diseases OBJECTIVES:Murine models of interleukin (IL)-23-driven spondyloarthritis (SpA) have demonstrated entheseal accumulation of γδT-cells which were responsible for the majority of local IL-17A production. However, IL-23 blockers are ineffective in axial inflammation in man. This study investigated γδT-cell subsets in the normal human enthesis to explore the biology of the IL-23/17 axis. METHODS:Human spinous processes entheseal soft tissue (EST) and peri-entheseal bone (PEB) were harvested during elective orthopaedic procedures. Entheseal γδT-cells were evaluated using immunohistochemistry and isolated and characterised using flow cytometry. RNA was isolated from γδT-cell subsets and analysed by qPCR. Entheseal γδT-cells were stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, anti-CD3/28 or IL-23 and IL-17A production was measured by high-sensitivity ELISA and qPCR. RESULTS:Entheseal γδT-cells were confirmed immunohistochemically with Vδ1 and Vδ2 subsets that are cytometrically defined. Transcript profiles of both cell populations suggested tissue residency and immunomodulatory status. Entheseal Vδ2 cells expressed high relative abundance of IL-23/17-associated transcripts including IL-23R, RORC and CCR6, whereas the Vδ1 subset almost completely lacked detectable IL-23R transcript. Following PMA stimulation IL-17A was detectable in both Vδ1 and Vδ2 subsets, and following CD3/CD28 stimulation both subsets showed IL-17A and IL-17F transcripts with neither transcript being detectable in the Vδ1 subset following IL-23 stimulation. CONCLUSION:Spinal entheseal Vδ1 and Vδ2 subsets are tissue resident cells with inducible IL-17A production with evidence that the Vδ1 subset does so independently of IL-23R expression. 10.1136/annrheumdis-2019-215210