In previous in vitro studies, we proposed a role for the extracellular matrix component, laminin-2, and its integrin receptor, VLA-6, in thymocyte development. The characterization oftwo dystrophic mouse strains with different defects in laminin-2 allowed us to examine thisproposal in vivo. Mice deficient in laminin-2, dy/dy, show a significant reduction in thymussize and number of thymocytes compared to normal littermates. These mice also exhibitedapparent alterations of thymic architecture. Examination of the CD4/CD8 populations in dy/dythymi showed large relative increases in the DN (CD4-CD8-) and SP (CD4+CD8-,CD4-CD8+) populations and a significant decrease in the DP (CD4+CD8+) population. Furtherexamination of the DN population for CD44 and CD25 expression showed a remarkabledecrease in the more mature pre-T cell populations. Analysis of apoptosis in situ, and by flowcytometry, in dy/dy thymi revealed a significant increase in apoptotic DN thymocytes in thecapsule and subcapsular regions. Interestingly, thymocyte development appeared to proceednormally in dystrophic mice expressing a mutant form of laminin-2, dy2J, as well as, in fetaland neonatal dy/dy mice. We propose that laminin-2 plays an active role in thymocyte developmentby delivering cell survival and differentiation signals at specific stages of developmentin young adult mice.

William J. Magner

Andrew C. Chang

Jennie  Owens

M-J. P. Hong

Andrew  Brooks

John E. Coligan

Aberrant Development of Thymocytesin Mice Lacking Laminin-2

Yves St-Pierre

Edouard E. Potworowski

T Cell Control of Extracellular Matrix Degradation

T lymphocytes constitute a highly dynamic tissue type. During the course of their lives, they
travel through a variety of physiological environments and experience a multitude of interactions
with extracellular matrix components and other cells. In order to do this, they must
receive many environmental cues, and translate these signals into the appropriate biological
actions. Particularly dramatic are the cytoskeletal shape changes a T cell must undergo during
the processes of leaving the bloodstream, migrating through tissues, and encountering antigen.
In this review, we highlight the role of integrins in providing a link between the extracellular
environment and cytoskeletal regulation and how these receptors help to orchestrate T
cell migration and antigen recognition.

Jennifer A. Epler

Rugao Liu

Yoji Shimizu

From the ECM to the Cytoskeleton and Back: How Integrins Orchestrate T Cell Action

Dendritic cells (DC) are antigen presenting cells (APC) with the unique ability to initiate an
immune response. Immature DC are localized in peripheral tissues where they exert a sentinel
function for incoming antigens (Ag). After Ag capture and exposure to inflammatory stimuli
DC undergo maturation and migrate to regional lymph nodes where the presentation of antigenic
peptides to T lymphocytes takes place. Thus their correct functioning as APC involves
localization in tissues and trafficking via the lymph or blood to lymphoid organs. In the
present study we have investigated the ability of DC to interact in vitro with human vascular
endothelial cells (EC) and extracellular matrix (ECM). DC are differentiated from monocytes
by in vitro exposure to GM-CSF and IL-13 for 7 days. In adhesion assays a considerable proportion
of DC binds to resting EC monolayers and this adhesion is inhibited by anti-CD11a
and CD11b, but not anti-CD11c mAbs. Binding to a natural ECM, derived from cultured EC
involves VLA-4 and VLA-5 integrins. In a transmigration assay, 10 % of input cells are able
to cross the EC monolayer in the absence of exogenous stimuli. The amount of DC transmigrated
through a monolayer of EC was increased of 2-3 fold by C-C chemokines RANTES,
MIP1α, and MIP-1β. Most importantly, in view of the trafficking pattern of these cells, a significant
proportion of DC can migrate in a reverse transmigration assay, i.e. across the
endothelial basement membrane and subsequently, across endothelial cells. Upon exposure to
immune or inflammatory signals peripheral DC undergo maturation and migration to lymphoid
organs. Functional maturation is associated with loss of responsiveness to chemokines
present at sites of inflammation (e.g. MIP1α, MIP1β and RANTES) and acquisition of a
receptor repertoire which renders these cells responsive to signals which guide their localization
in lymphoid organs (e.g. MIP3β). A better understanding of the molecular basis of DC
trafficking may provide molecular and conceptual tools to direct and modulate DC localization
as a strategy to upregulate and orient specific immunity.

Giancarlo Bianchi

Giovanna D'amico

Luisella Varone

Silvano Sozzani

Alberto Mantovania

Paola Allavena

In Vitro Studies on the Trafficking of Dendritic Cells
Through Endothelial Cells and Extra-Cellular Matrix

Degradation of the extracellular matrix occurs under physiological and pathological conditions,thought to be principally mediated by a family of neutral proteolytic enzymes termedthe matrix metalloproteinases (MMPs). The present study was initiated to determine whethermast cells have the ability to produce these proteases in diseased and normal human tissue.Immunohistochemistry and in situ hybridization was performed to localize interstitial collagenaseprotein and mRNA transcripts in diseased human tissue. The human mast cell lineHMC-1 was cultured under serum free conditions, stimulated with phorbol mystrate acetate(PMA) and supernatants analyzed by Western blotting and zymography to determine the profileof secreted MMPs. The dog mast cell line BR, known to secrete gelatinolytic enzymes,was used in parallel studies. Total RNA was extracted and analyzed by RT-PCR for theexpression of tissue inhibitors of MMP (TIMPs). Collagenase-1 protein and mRNA wereexpressed by tryptase and chymase positive human mast cells in all tissue analyzed. This proteinasewa also detected in the cytoplasm and conditioned media of HMC-1 cells. PMAinduced gelatinolytic activity in both mast cell lines examined. TIMP-1 immunoreactivitywas detected and TIMP-1, and-2 (but not TIMP-3) mRNA transcripts were amplified fromHMC-1 cells. This is the first demonstration of the expression of collagenase-1 by humanmast cells in both inflamed and normal tissues, and by a human mast cell line. MMPs secretedby these cells could contribute to the extensive matrix lysis characteristic of diseases such asrheumatoid arthritis and inflammatory ocular disorders. Alternatively collagenase-1 productionby mast cells may play a critical role in cell invasion and migration into sites of inflammation.

Nick  Di Girolamo

Denis  Wakefield

In vitro and in vivo Expression of InterstitialCollagenase/MMP-1 by Human Mast Cells

The immune system has a remarkable capacity to maintain a state of equilibrium even as it
responds to a diverse array of foreign proteins and despite its contact exposure to self-antigens.
Apoptosis is one of the mechanisms aimed at preserving the homeostasis after the completion
of an immune response, thus returning the immune system to a basal state and
warranting the elimination of autoagressive cells in both central and peripheral lymphoid
organs. Targeted deletions in critical genes involved in the apoptotic death machinery
together with natural spontaneous mutations have clearly shown the importance of apoptosis
in the regulation of the immune response. This complex scenario of stimulatory and inhibitory
genes has been enriched with the finding that galectin-1, a 14.5 kDa β-galactoside-binding
protein, is able to induce apoptosis of immature cortical thymocytes and mature T cells by
cross-linking cell surface glycoconjugates. Galectin-1 is present not only in central and
peripheral lymphoid organs, but also at sites of immune privilege. In the present article we
will discuss the implications of galectin-1-induced apoptosis in T-cell physiopathology in an
attempt to validate its therapeutic potential in autoimmune and inflammatory diseases.

C. E. Sotomayor

G. A. Rabinovich

“Galectin-1 Induces Central and Peripheral Cell Death:
Implications in T-Cell Physiopathology”

Leukocyte extravasation into perivascular tissue during inflammation and lymphocyte homingto lymphoid organs involve transient adhesion to the vessel endothelium, followed by transmigrationthrough the endothelial cell (EC) layer and establishment of residency at the tissue sitefor a period of time. In these processes, leukocytes undergo multiple attachments to, and detachmentsfrom, the vessel-lining endothelial cells, prior to transendothelial cell migration. Transmigratingleukocytes must traverse a subendothelial basement membrane en route to perivasculartissues and utilize enzymes known as matrix metalloproteinases to make selective clips in theextracellular matrix components of the basement membrane. This review will focus on the evidencefor a link between adhesion of leukocytes to endothelial cells, the induction of matrixmetalloproteinases mediated by engagement of adhesion receptors on leukocytes, and the abilityto utilize these matrix metalloproteinases to facilitate leukocyte invasion of tissues. Leukocyteswith invasive phenotypes express high levels of MMPs, and expression of MMPsenhances the migratory and invasive properties of these cells. Furthermore, MMPs may be usedby lymphocytes to proteolytically cleave molecules such as adhesion receptors and membranebound cytokines, increasing their efficiency in the immune response. Engagement of leukocyteadhesion receptors may modulate adhesive (modulation of integrin affinities and expression),synthetic (proteinase induction and activation), and surface organization (clustering of proteolyriccomplexes) behaviors of invasive leukocytes. Elucidation of these pathways will lead tobetter understanding of controlling mechanisms in order to develop rational therapeuticapproaches in the areas of inflammation and autoimmunity.

Joseph A. Madri

Donnasue  Graesser

Cell Migration in the Immune System: the EvolvingInter-Related Roles of Adhesion Molecules andProteinases

The extracellular matrix (ECM) as well as soluble mediators like cytokines can influence thebehavior of cells in very distinct as well as cooperative ways. One group of ECM moleculeswhich shows an especially broad cooperativety with cytokines and growth factors are the proteoglycans.Proteoglycans can interact with their core proteins as well as their glycosaminoglycanchains with cytokines. These interactions can modify the binding ofcytokines to their cell surface receptors or they can lead to the storage of the soluble factors inthe matrix. Proteoglycans themselves may even have cytokine activity. In this review wedescribe different proteoglycans and their interactions and relationships with cytokines andwe discuss in more detail the extracellular regulation of the activity of transforming growthfactor-&#946; (TGF-&#946;) by proteoglycans and other ECM molecules. In the third part the interactionof heparan sulfate chains with fibroblast growth factor-2 (FGF-2, basic FGF) as a prototypeexample for the interaction of heparin-binding cytokines with heparan sulfate proteoglycansis presented to illustrate the different levels of mutual dependence of the cytokine networkand the ECM.

Elke  Sch&#246;nherr

Heinz-J&#252;Rgen  Hausser

Extracellular Matrix and Cytokines: A Functional Unit

Intrathymic injection of the Abelson murine leukemia virus (A-MuLV) results in transformationof immature T and B lymphoid cells. In this report we demonstrate that the concentrationof A-MuLV injected into murine thymi influences the selection of the transformation target.Thus, concentrated A-MuLV gives rise to Thy-1+ B220- thymomas. In contrast, dilute virusinduces B220+ thymomas that also express low levels of Thy- 1 (Thy-1lo), a phenotype that issimilar to marrow-derived progenitor B-lymphoid cells (pro-B cells) that are highly susceptibleto A-MuLV transformation invitro. However, rare B220+ lymphoid cells isolated fromnormal adult thymi were not transformed by A-MuLV invitro, while B220+ cells isolatedfrom bone marrow were highly susceptible to transformation by A-MuLV. The Thy-1loB220+population in the primary thymomas had not rearranged TCR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mtext>&#x03B3;</mml:mtext></mml:math>, TCR&#946;, or <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>I</mml:mi><mml:mi>g</mml:mi><mml:mtext>&#x03BA;</mml:mtext></mml:mrow></mml:math> genes, butcontained subpopulations that assembled Ig DJH or VDJH genes and were therefore similar totransformed pro- and pre-B cells obtained from A-MuLV infected fetal liver and adult bonemarrow, respectively. However, unlike A-MuLV-transformed pro- and pre-B cells, many (40&#8211;70&#37;) of the Thy-1lo B220+ transformed thymoma cells had not rearranged Igh genes, andtherefore appear to represent undifferentiated lymphoid cells. We conclude that A-MuLV maytransform an undifferentiated lymphoid target in the thymus.

Eric Y. Chen

Bradley J. Swanson

Steven S. Clark

Transformation of Undifferentiated Thy-1lo B220+ Thymic Lymphoid Cells by the Abelson Murine Leukemia Virus

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Journal of Immunology Research provides a platform for scientists and clinicians working in different and diverse areas of immunology and therapy.

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Chief Editor, Professor Holland, has a background focusing on researching the development of conjunctival fibrosis and the characterisation of immune responses to potential C. trachomatis vaccine candidates.

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Journal of Immunology Research - Table of contents 2000

title

Journal of Immunology Research provides a platform for scientists and clinicians working in different and diverse areas of immunology and therapy.

Journal of Immunology Research