Distribution of beta 7 integrins in human intestinal mucosa and organized gut-associated lymphoid tissue.

Two alternative integrins involved in mucosal homing (alpha 4 beta 7) or epithelial retention (alpha E beta 7) of lymphocytes were examined in the human gut. The distribution of the beta 7 subunit [monoclonal antibody (mAb) M301] was bimodal in that it was strongly expressed by alpha E beta 7 + cells but weakly by alpha 4 beta 7 + cells. More than 90% of intraepithelial lymphocytes (IEL), including the minor subsets of CD4+, T-cell receptor (TCR) gamma/delta +, and CD3- cells, expressed alpha E beta 7 as did most lamina propria CD8+ (88%) and a fraction (36%) of CD4+ lymphocytes. Conversely, B-lineage cells (CD19+) and macrophages (CD68+) were negative. In gut-associated lymphoid tissue (GALT: Peyer's patches and appendix) only a few (< 5%) cells were positive for alpha E beta 7 (confined to CD8+ lymphocytes and CD11c+ putative dendritic cells). A relatively small fraction of IEL (30-50%) expressed alpha 4 beta 7 (mAb Act-1), while most (70%) lamina propria T and B lymphocytes, blasts, plasma cells and macrophages were positive. In GALT, T lymphocytes expressed similar levels of alpha 4 beta 7 as in the lamina propria whereas relatively few B lymphocytes (< 50%) were positive. Isolated lamina propria CD8+, CD4+, CD19+, and CD38+ cells contained mRNA for alpha 4 and the former three subsets as well as appendix CD8+ cells also for beta 7 while only lamina propria CD8+ cells had mRNA for alpha E. Together, the results suggested that alpha E beta 7 and alpha 4 beta 7 are differentially regulated in inductive sites and effector sites of the human gut. Because lymphoid cells at both sites expressed mainly alpha 4 beta 7, this integrin may be a homing receptor on memory and effector cells bound for lamina propria as well as on naive lymphocytes extravasating in GALT. Conversely, because alpha E beta 7 was mainly expressed by CD8+ cells in epithelium and lamina propria, it was probably induced after extravasation, in agreement with the observation that IEL and a fraction of lamina propria T lymphocytes (mainly CD8+ cells) generally expressed higher levels of beta 7 than most CD4+ and B cells. Also a subset of putative dendritic cells located near the follicle-associated epithelium of GALT expressed alpha E beta 7, perhaps reflecting epithelial interaction during primary immune responses.     

Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin

The integrin alpha4beta7 binds to MAdCAM-1 and contributes to homing of lymphocytes to gut and other mucosal tissues. In humans, the alpha4beta7(hi) subset of circulating memory cells appears to have been primed in mucosal tissues. The factors that determine whether alpha4beta7(lo) naive cells become alpha4beta(hi) or alpha4beta7(-) cells upon differentiation are poorly understood but could include an influence of the activating antigen-presenting cell. To address this point, the induction of alpha4beta7 following activation of mouse cells with the APC-dependent stimulus soluble anti-CD3 has been examined. Almost all mouse T cells freshly isolated from mesenteric lymph nodes (MLN) and peripheral (PLN; axillary, brachial and inguinal) lymph nodes stained only weakly for alpha4beta7 but a subpopulation became alpha4beta7(hi) upon activation with anti-CD3 in a cell cycle- and accessory cell-dependent manner. A small proportion (approximately 1.5 %) of the starting cells gave rise to alpha4beta7(hi) cells after culture. A higher proportion of alpha4beta7(hi) cells were generated in MLN than PLN cultures. Peyer's patch cultures gave intermediate values. In crossover experiments, MLN dendritic cells (DC) induced higher proportions and numbers of alpha4beta7(hi) cells than PLN DC irrespective of the source of T cells. Therefore, in addition to their other immunoregulatory roles, DC have the potential to shape immune responses by influencing the homing of the lymphocytes they activate.     

Cell Adhesion Molecule and Lymphocyte Activation Marker Expression during Experimental Vaginal Candidiasis

Cell-mediated immunity by Th1-type CD4(+) T cells is the predominant host defense mechanism against mucosal candidiasis. However, studies using an estrogen-dependent murine model of vaginal candidiasis have demonstrated little to no change in resident vaginal T cells during infection and no systemic T-cell infiltration despite the presence of Candida-specific systemic Th1-type responses in infected mice. The present study was designed to further investigate these observations by characterizing T-cell activation and cell adhesion molecule expression during primary and secondary C. albicans vaginal infections. While flow cytometry analysis of activation markers showed some evidence for activation of CD3(+) draining lymph node and/or vaginal lymphocytes during both primary and secondary vaginal Candida infection, CD3(+) cells expressing the homing receptors and integrins alpha(4)beta(7), alpha(M290)beta(7), and alpha(4)beta(1) in draining lymph nodes of mice with primary and secondary infections were reduced compared to results for uninfected mice. At the local level, few vaginal lymphocytes expressed integrins, with only minor changes observed during both primary and secondary infections. On the other hand, immunohistochemical analysis of vaginal cell adhesion molecule expression showed increases in mucosal addressin cell adhesion molecule 1 and vascular cell adhesion molecule 1 expression during both primary and secondary infections. Altogether, these data suggest that although the vaginal tissue is permissive to cellular infiltration during a vaginal Candida infection, the reduced numbers of systemic cells expressing the reciprocal cellular adhesion molecules may preempt cellular infiltration, thereby limiting Candida-specific T-cell responses against infection.     

The human intraepithelial lymphocyte marker HML-1 is an integrin consisting of a beta 7 subunit associated with a distinctive alpha chain.

The membrane antigen defined by the monoclonal antibody (mAb) HML-1 is abundantly expressed on, and largely restricted to, the T cells which populate the intestinal epithelium. We show that the mature form of the antigen is a heterodimer comprising a 150-kDa alpha chain and a 120-kDa beta chain. Direct sequencing of tryptic peptides cleaved from the purified beta chain identified this polypeptide with the integrin beta 7 isotype. cDNA clones coding for the beta 7 chain have recently been isolated from T cell cDNA libraries, but the beta 7 chain had not been identified at the protein level. No information is available concerning the primary structure of the HML-1 alpha chain. We show that this subunit is synthesized as a precursor form that undergoes, like several other integrin alpha subunits, a post-translational cleavage of a peptide bond. Among the 11 human integrin alpha chains previously identified, 10 have biochemical features and/or a distribution different from those of HML-1 alpha. One, VLA alpha 4 (CD49d), has a molecular mass of 150 kDa and is expressed on HML-1+ cells but is not recognized by HML-1 mAb. We conclude that HML-1 is a novel member of the integrin family made of the beta 7 chain and of an as-yet-undescribed human alpha chain characterized by the post-translational cleavage of a 10-kDa peptide. HML-1 is, thus, probably the human counterpart of the mouse antigen M290.     

Preferential expression of the mucosal homing receptor integrin alpha 4 beta 7 in gastrointestinal non-Hodgkin's lymphomas.

Recent studies have identified the integrin alpha 4 beta 7 as a mucosal homing receptor that mediates lymphocyte migration to the intestinal mucosa by binding to MAdCAM-1, a vascular recognition molecule (addressin) selectively expressed on mucosal endothelium. In the present study, we have assessed the expression of alpha 4 beta 7 on B- and T-cell non-Hodgkin's lymphomas of different primary localization and on related normal lymphocytes. Among B-lineage lymphomas, expression of alpha 4 beta 7 was present in the majority of cases of malignant lymphomatous polyposis of the intestine and low-grade lymphoma of the mucosa-associated lymphoid tissue/monocytoid B-cell lymphoma and in some cases of precursor B-cell lymphoma. CLL/small lymphocytic lymphoma, (nodal) mantle cell lymphoma, follicular center cell lymphoma, Burkitt's lymphoma, and diffuse large B-cell lymphoma were virtually always alpha 4 beta 7 negative, as was the case when localized in the mucosa-associated lymphoid tissue. The normal B cells of the follicle mantles and part of the B cells of the extrafollicular B-cell compartment of lymphoid tissues expressed moderate levels of alpha 4 beta 7. By contrast, follicular center cells were alpha 4 beta 7 negative. Among T-lineage lymphomas, expression of alpha 4 beta 7 was also strongly related to the primary localization; in mucosal, nodal, and cutaneous T cell lymphomas the percentage of positive cases was 56%, 17%, and 0%, respectively. All cases of precursor T-cell lymphoma were alpha 4 beta 7 negative. High expression of alpha 4 beta 7 was found on a subset of peripheral blood memory T cells as well as on lymphocytes in the intestinal mucosa. We conclude that non-Hodgkin's lymphomas that are related to mucosa-associated B- and T-lymphocyte populations selectively express the mucosal homing receptor alpha 4 beta 7. The presence of this receptor underscores their distinctive character and may play an important role in determining their characteristic mucosal dissemination pattern.     

The mucosal T cell integrin αM290β7 recognizes a ligand on mucosal epithelial cell lines

The integrin α_M290β7 is expressed at high levels on mucosal T cells, particularly on those within the epithelium of the gut. We now report that a mouse T cell hybridoma, MTC-1, with similar surface expression of this molecule, adhered strongly to cells of the mouse rectal carcinoma line CMT93 and that adhesion was blocked completely by the monoclonal antibody (mAb) M290. Other mAb to the α_M290 or β7 subunits had little or no inhibitory effect. M290 also inhibited adhesion of the hybridoma to cells of the mouse lung carcinomas CTM64/61 and KLN205 but had little or no effect on adhesion to seven other mouse epithelial cell lines or to the human colon carcinoma line, HT29. Intraepithelial lymphocytes (IEL) isolated from the small intestine of BALB/c mice displayed potent Tcell receptor-dependent cytotoxic effector function against CMT93 in the presence of low concentrations of Phytolacca americana lectin. This cytotoxic activity also was inhibited by the M290 mAb. Treatment of CMT93 cells with tumor necrosis factor-a and interferon-γ induced expression de novo of ICAM-1 and reduced the inhibitory effect of M290 in tests both for adhesion and cytotoxicity. In further experiments cytotoxic activity of IEL against the mastocytoma P815 was investigated. This target cell was considered not to possess a ligand for the integrin. In this case cytotoxic effector function was triggered by anti-CD3 mAb and, in contrast to results with CMT93, target cell lysis was increased in the presence of M290 and other antibodies to the integrin, suggesting a co-stimulatory effect. These results show that α_M290β7 recognizes a ligand on the surface of certain epithelial cell lines. Further, they provide the first clear indication that this integrin may play an important role in functional interactions between T cells and the mucosal epithelium.     

Leucocyte recruitment during enteric nematode infection

Resolution of infection with the intestinal nematode Trichinella spiralis depends on the host mounting a T helper 2 (Th2) response. It is known that both mast cells and T cells play a crucial role. We have previously shown that efficient migration of mast cells to the gut during infection depends on their expression of the integrin beta 7. beta 7 forms a heterodimer complex with either alpha E or alpha 4 integrin chains, alpha E beta 7 binding to E-cadherin expressed by epithelial cells and alpha 4 beta 7 binding to mucosal addressin cell adhesion molecule (MAdCAM-1) on the endothelium. We were interested to know whether dysfunctional mast cell localization to the gut in the absence of beta 7 was due to the failure of alpha 4 beta 7 to bind to MAdCAM-1 or the failure of alpha E beta 7 to bind to E-cadherin. We used blocking monoclonal antibodies against alpha E (M290) or alpha 4 (PS2) or beta 7 (HB293) during T. spiralis infection of C57BL/6 mice and found that all antibody treatments reduced mastocytosis. In contrast, none of the antibody treatments prevented the migration of CD3(+) T cells into the intestine. These results indicate that during inflammation (a) there is integrin redundancy for lymphocytes but not for mast cells and (b) both alpha E beta 7 and alpha 4 beta 7 are crucial either for the entry of mast cells into the gut or for their maturation once they have entered.     

In vitro exposure to highly cytopathic HIV-1 X4 strains increases expression of mucosa-associated integrins on CD4(+) T cells

To determine whether infection with HIV-1 strains of different tropisms would influence expression of the mucosa-associated integrins alpha 4 beta 7 and alpha E beta 7 or the lymph node homing receptor L-selectin on peripheral T lymphocytes, cells were infected with the CXCR4-tropic (X4)/syncytium-inducing (SI) HIV-1(IIIB) strain or with X4/SI or CCR5-tropic (R5)/non-SI (NSI) primary human isolates. Flow cytometric analyses of CD4(+) T cells from cultures infected with HIV-1(IIIB) and one X4/SI primary HIV-1 isolate revealed a significant increase in surface expression of alpha 4 beta 7 and alpha E beta 7 12 days after infection. L-selectin expression was not significantly affected on CD4(+) T cells. However, infection with another X4/SI and two R5/NSI primary HIV-1 isolates did not significantly alter homing receptor expression on CD4(+) T cells. Since a higher degree of CD4 cytopathicity occurred in those cultures having increased integrin expression, these data suggest that significantly altered mucosal homing receptor expression on CD4(+) T cells may result as a "bystander" effect after infection with some cytopathic isolates of HIV-1.     

A new surface antigen on intraepithelial lymphocytes in the intestine

A new surface molecule has been discovered on mouse intestinal intraepithelial lymphocytes (IEL) using a rat anti-mouse IEL monoclonal antibody, M290. It was expressed at high levels on nearly all IEL and on a majority of T cells in the gut lamina propria. M290 stained, with lower intensity, a small minority of T cells in other lymphoid tissues. Expression was biased towards the CD8+ subset. Stimulation of peripheral T cells with mitogens did not induce expression of the new antigen but addition of transforming growth factor beta to stimulated T cells had a marked inductive effect. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of IEL surface components precipitated with M290 showed principal bands at 135, 120, 28 and 24 kDa (reduced) and 135, 100, 24 and 21 kDa (nonreduced). Precipitation with antibodies to integrin subunits showed that the new molecular complex was not a member of the beta 1, beta 2, or beta 3 integrin families although all of these were represented on IEL. A 13-amino acid N-terminal sequence obtained from the 120-kDa beta subunit of the antigen prepared from an M290+ T hybridoma (MTC-1) did not show homology with integrins. Pulse-chase studies using MTC-1 cells showed that the 135-kDa alpha subunit was derived from a 147-kDa precursor. The function of this new molecular complex is not yet known.     

Ly-49 antigen defines an alpha beta TCR population in i-IEL with an extrathymic maturation.

In this paper we describe a monoclonal antibody, JR9-318, which was obtained from a wild-derived mouse immunized with the M14T cell line (CD3+CD4-CD8-) in order to describe antigenic molecules expressed during T cell differentiation. This mAb precipitated a protein from the M14T cell line or subclones that migrates like a T cell receptor heterodimer at 85-90 kDa under non-reducing conditions and 45-50 kDa under reducing conditions. The molecular characteristics of this antigen and the data obtained by sequential immunoprecipitation led us to conclude that JR9-318 mAb recognizes the Ly-49 molecule already described. Using direct immunofluorescence staining, this mAb was shown to identify a small population of cells in the adult thymus but not in the spleen, lymph node or bone marrow of most laboratory mouse strains. The phenotypic characteristics of this thymic subpopulation do not correspond to those of any other known classical population. A more prominent population of CD3+ alpha beta+ T cells is stained by this mAb in intestinal intra-epithelial lymphocytes with a peculiar phenotype, different from the one found in the thymus. These cells express V beta families usually deleted in the thymus of BALB/c mice. We discuss here the origin of these T cell subpopulations and the possible maturation of T cells without thymic influence.     

Topographic distribution of homing receptors on B and T cells in human gut-associated lymphoid tissue: relation of L-selectin and integrin alpha 4 beta 7 to naive and memory phenotypes.

In mice, integrin alpha 4 beta 7 is the main receptor used by lymphocytes that home to the Peyer's patches, although L-selectin contributes to the initial interaction with high endothelial venules. Less is known about the expression and function of these adhesion molecules in humans. The distribution of L-selectin and alpha 4 beta 7 on various B- and T-cell subsets was examined in human Peyer's patches (n = 8) and appendix (n = 4), collectively called gut-associated lymphoid tissue. Multicolor immunophenotyping was performed on cryosections, and dispersed cells were examined by flow cytometry. In cryosections, CD45RA+ T cells around and within interfollicular high endothelial venules, as well as surface (s)IgD+ B lymphocytes in the follicle mantles, often expressed abundant L-selectin but only intermediate levels of alpha 4 beta 7. CD45RO+ T cells and sIgD- B cells expressed higher levels of alpha 4 beta 7 and were often located near putative efferent lymphatics; only a small fraction (< 20%) of such memory cells expressed L-selectin. By flow cytometry, considerably more T than B lymphocytes co-expressed L-selectin and alpha 4 beta 7 (40% versus 25% and 67% versus 39%, respectively). In samples with many L-selectin+ cells (> 30%), more of these lymphocytes co-expressed alpha 4 beta 7 than in samples with few L-selectin+ cells. Because L-selectin and alpha 4 beta 7 were co-expressed on lymphocytes located near high endothelial venules, and because such co-expression was relatively common when many L-selectin+ cells were present, both of these molecules might participate in homing to human gut-associated lymphoid tissue. Such homing is probably most pronounced for T lymphocytes that were found to express L-selectin and alpha 4 beta 7 more often than B lymphocytes. The selective and relatively high expression of alpha 4 beta 7 on memory cells located near efferent lymphatics indicated a different migratory capacity; after exit from gut-associated lymphoid tissue, such stimulated cells might home mainly to mucosal effector sites.     

Expression of mucosal homing receptor alpha4beta7 is associated with enhanced migration to the Chlamydia-infected murine genital mucosa in vivo

The CD4 T helper cell type 1 (Th1) response is essential for the resolution of chlamydial genital infection in mice. However, not all Th1 clones are equally protective in eradicating the infection. Since oral immunization regimens produce protective immunity, we evaluated the role of the mucosa-associated homing receptor, alpha4beta7, in trafficking to the genital mucosa. Using a panel of CD4, Th1 cell lines and clones, we compared the lymphocyte homing patterns of a Chlamydia-specific, protective clone (P-MoPn), a nonprotective clone (N-MoPn), and a keyhole limpet hemocyanin (KLH)-specific cell line (KLH-1). T cells were labeled with the fluorescent dye PKH-26, adoptively transferred into Chlamydia-infected mice, and monitored at different time points throughout the course of a genital infection. We found that clones P-MoPn and N-MoPn migrated to similar extents to the genital tract and in significantly greater numbers than the KLH-specific T-cell line. Both clones and the KLH-1 line expressed similar levels of the adhesion molecules alpha4, beta1, CD44, and CD11a. However, clones P-MoPn and N-MoPn expressed higher levels of the mucosal homing receptor, alpha4beta7. Also, clones P-MoPn and N-MoPn but not the KLH-1 line migrated to the mesenteric lymph node, suggesting a mucosal recirculation pattern. Moreover, blocking alpha4beta7 adhesion interaction in vivo significantly reduced the recruitment of P-MoPn but not KLH-1 to the genital tract. These findings show that the mucosal homing receptor alpha4beta7 is utilized by a subset of CD4 cells during migration to the Chlamydia-infected genital tract.     

Loss of expression of alpha4beta7 integrin and L-selectin is associated with high-grade progression of low-grade MALT lymphoma.

Expression of adhesion molecule in low-grade B-cell mucosa-associated lymphoid tissue (MALT) lymphoma of the gastrointestinal tract has been reported in recent years, but these reports have primarily focused on low-grade gastrointestinal MALT lymphoma. In this study, we examined the lymphocytic homing receptor alpha4beta7 integrin, L-selectin, and VLA-4 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in low-grade lymphoma of the gastrointestinal tract and other organs such as the ocular adnexa and thyroid. We also observed changes in the expression pattern associated with high-grade transformation. Neoplastic cells in the gastrointestinal low-grade lymphoma and the low-grade component of high-grade MALT lymphoma were found to be alpha4beta7 integrin(+), L-selectin(+), whereas the gastrointestinal high-grade component and diffuse large B-cell lymphoma were found to be alpha4beta7 integrin(-), L-selectin(-). High endothelial venules in the gastric MALT lymphomas expressed MAdCAM-1. In the ocular adnexa low-grade MALT lymphoma, most cases were alpha4beta7 integrin(-), L-selectin(+); and in the thyroid, most cases of both low- and high-grade MALT lymphoma were alpha4beta7 integrin(-), L-selectin(-). These findings show that alpha4beta7 integrin and L-selectin may play an important role in the lymphocyte homing of gastrointestinal low-grade MALT lymphoma and in the loss of alpha4beta7 integrin expression throughout the course of high-grade progression.     

Integrins alpha4beta7 and alphaEbeta7 are expressed on epidermotropic T cells in cutaneous T cell lymphoma and spongiotic dermatitis.

Integrin alpha4beta7 has been associated with tissue-specific homing of malignant and inflammatory lymphocytes to gastrointestinal mucosa, whereas integrin alphaEbeta7 has been associated with intraepithelial lymphocytes in both the gut and the skin. This prompted us to examine the expression of alpha4beta7 on skin-infiltrating lymphocytes in 12 cases of patch/plaque stage cutaneous T cell lymphoma (CTCL) and in 4 cases of spongiotic dermatitis, which also display intraepidermal T cell accumulation. alpha4beta7 was found to be expressed on 64.8+/-7.4% of intraepidermal and 39.1+/-5.0% of intradermal T lymphocytes in CTCL. There was a significant positive correlation (r=0.58) between the degree of epidermotropism and the percentage of intraepidermal T cells expressing alpha4beta7. Similar findings were observed in spongiotic dermatitis, indicating that this result is not unique to malignant T cells. We evaluated staining of T cells in the same specimens for presence of alphaEbeta7 and observed a strong correlation between the expression of both beta7 integrins in each specimen. Staining with antibodies directed against the known ligands of alpha4beta7 was also performed on skin biopsies from CTCL patients. There was significantly increased dermal microvascular endothelial expression of vascular cell adhesion molecule-1 in lesional compared with nonlesional skin, and in nonlesional skin compared with skin of normal control subjects. Dermal and epidermal expression of the CS-1 domain of fibronectin was present but not increased in lesional biopsies compared with nonlesional or normal controls, whereas expression of mucosal addressin cell adhesion molecule-1 was not detectable in any skin biopsy specimens. In summary, alpha4beta7, like alphaEbeta7, is expressed at high levels on epidermotropic T cells and may interact with endothelial cell vascular cell adhesion molecule-1 as part of stepwise recruitment of lymphocytes from the blood to the epidermis.     

Expression of the mucosal T cell integrin αM290β7 by a major subpopulation of dendritic cells in mice

Dendritic interdigitating cells isolated from lymph nodes, Langerhans' cells from skin and dendritic cells from the spleen have been tested for expression of the mucosal T cell integrin αM290β7. Almost all interdigitating cells isolated from mesenteric lymph nodes expressed the integrin at high levels; 50-60% of those from lymph nodes draining non-mucosal sites also expressed this adhesion molecule. In contrast, α_M290β7 was not detected on either Langerhans' cells or splenic dendritic cells. Because this integrin has recently been shown to recognize a ligand that seems to be expressed mainly or exclusively by epithelial cells, it is proposed that this adhesion pathway may be important for antigen sampling by dendritic cells in mucosal tissues.     

Expression of lymphocyte homing receptors and vascular addressins in low-grade gastric B-cell lymphomas of mucosa-associated lymphoid tissue.

In this study, we examined lymphocyte homing receptor and vascular addressin expression in a case of primary gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) with a secondary intestinal spread. We compared the findings with that observed in B cells of normal MALT and MALT acquired as a consequence of Helicobacter pylori-associated gastritis and other low-grade gastric B-cell MALT lymphomas. The neoplastic B cells in the gastric tumor were alpha 4 beta 7-, CD62L+, whereas the intestinal secondary was alpha 4 beta 7+, CD62L-. Incubation of isolated tumor cells from the stomach by H. pylori generated T-cell-dependent proliferation of neoplastic B cells and induced expression of alpha 4 beta 7 integrin similar to the intestinal tumor. These observations indicate that reversal of homing receptor profile in the gastric tumor by antigen specific stimulation may be responsible for secondary intestinal dissemination. In normal stomach and normal MALT, alpha 4 beta 7 and CD62L expression reflected the differentiation of the B cell. Plasma cells were alpha 4 beta 7+, CD62L-, whereas a subset of memory B cells were alpha 4 beta 7-, CD62L+. Homing receptor expression in MALT lymphoma B cells was heterogeneous, however, in line with their memory B-cell phenotype in the majority of cases, the neoplastic B cells were alpha 4 beta 7-, CD62L+. Neoplastic plasma cells were always alpha 4 beta 7+, CD62L-. The venules in normal gastric mucosa expressed mucosal addressin cell adhesion molecule-1 but not peripheral lymph node addressin. In normal MALT, H. pylori-associated follicular gastritis and MALT lymphomas high endothelial venules coexpressed mucosal addressin cell adhesion molecule-1 and peripheral lymph node addressin. These findings suggest expression of lymphocyte homing receptors by B cells and vascular addressins by mucosal venules are similar in normal MALT and MALT lymphomas, and factors controlling normal mucosal B-cell traffic are also operational in MALT lymphomas.     

Islet beta-cell-specific T cells can use different homing mechanisms to infiltrate and destroy pancreatic islets

Organ infiltration by T cells depends on the adhesion molecules expressed in these sites and on homing receptors expressed by the T cells. Here, we have studied which form of priming can enable T cells to home to pancreatic islets. To this end, we have used transgenic mice expressing the model autoantigen ovalbumin in pancreatic islets and transgenic ovalbumin-specific CD4 and CD8 T cells. We demonstrate that these T cells were imprinted with homing receptor patterns characteristic for the site of priming, such as alpha4beta7 integrin for mucosal antigen delivery or functionally active alpha4beta1 integrin for islet autoantigens. The adhesion molecules corresponding to these receptors were found to be constitutively expressed in islets, enabling T cells bearing these receptors to infiltrate the islets and to cause diabetes. Disease was prevented only by blockade of the endothelial adhesion molecule, ligand of homing receptors with which the T cells were imprinted. Thus, different priming locations induced different homing mechanisms, allowing T cells to target the islets. This may contribute to the susceptibility of islets to T-cell-mediated attack. Furthermore, it may pertain to the design of adhesion-modulating therapies alone or in combination with external autoantigen administration.     

L-selectin and alpha 4 beta 7 integrin homing receptor pathways mediate peripheral lymphocyte traffic to AKR mouse hyperplastic thymus.

Before the development of thymic lymphoma, AKR mice undergo a striking lymphoid hyperplasia of the thymic medulla. We have previously shown that there is a marked increase in traffic of B and T lymphocytes from the periphery into the preneoplastic, hyperplastic thymuses of these mice, in contrast to the scant traffic of such cells to normal thymuses. The traffic of lymphocytes to lymph nodes and Peyer's patches is controlled in part by the interaction of lymphocyte adhesion molecules called homing receptors with their tissue-selective endothelial ligands known as vascular addressins. We have investigated the roles of homing receptors and vascular addressins in the traffic of lymphocytes to the AKR hyperplastic thymus. We demonstrate that development of hyperplasia is accompanied by an increase in the number of thymic medullary blood vessels with high endothelial venule morphology and expression of the peripheral node addressin (PNAd) and the mucosal addressin (MAdCAM-1). In vitro and in vivo functional assays show that the addressin/homing receptor pairs PNAd/L-selectin and MAdCAM-1/alpha 4 beta 7 are involved in lymphocyte traffic to the hyperplastic thymus. These results indicate that molecular adhesion mechanisms involved in tissue-selective migration of lymphocytes to peripheral lymph node and to mucosal lymphoid tissues play a role in the recruitment of B and T lymphocytes to the AKR thymus and thus in the pathogenesis of thymic hyperplasia.     

Lymphocyte binding to MAdCAM-1 via alpha4beta7 integrin activates a signal transduction pathway involving tyrosine phosphorylation of paxillin and p105(Cas-L)

Alpha4beta7 integrin mediates lymphocyte trafficking to mucosal lymphoid organs by interacting with the mucosal vascular addressin MAdCAM-1. While the structural basis for the alpha4beta7 integrin-MAdCAM-1 interaction has been well characterized, less is known about the signal transduction pathways that regulate the alpha4beta7 integrin-mediated lymphocyte interaction with MAdCAM-1-expressing endothelial cells. Here we demonstrate that ligation of alpha4beta7 integrin with MAdCAM-1 induces a prominent tyrosine phosphorylation of paxillin and a 105-kDa protein (p105) that is reactive with an anti-p130(Cas) antibody, in the mouse T-cell line TK-1. Cloning and expression of a full-length cDNA encoding the mouse p105(Cas-L) revealed that the p105 molecule is a mouse ortholog of p105(Cas-L). We also demonstrated that crosslinking of alpha4beta7 integrin with MAdCAM-1 induces the rapid tyrosine phosphorylation of paxillin and p105(Cas-L) in normal lymphocytes and that PMA stimulation enhances the tyrosine phosphorylation of p105(Cas-L) but not of paxillin. These results suggest that intracellular signals initiated by alpha4beta7 integrin involve the tyrosine phosphorylation of paxillin and p105(Cas-L), which are differentially regulated, at least in part, by mechanisms that are PMA-sensitive or -insensitive.