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W L Havran

Publications and source records attributed to W L Havran.

At least 19 recordsLinked to original sources
PubMed1999

Positive and negative regulation of V(D)J recombination by the E2A proteins.

A key feature of B and T lymphocyte development is the generation of antigen receptors through the rearrangement and assembly of the germline variable (V), diversity (D), and joining (J) gene segments. However, the mechanisms responsible for regulating developmentally ordered gene rearrangements are largely unknown. Here we show that the E2A gene products are essential for the proper coordinated temporal regulation of V(D)J rearrangements within the T cell receptor (TCR) gamma and delta loci. Specifically, we show that E2A is required during adult thymocyte development to inhibit rearrangements to the gamma and delta V regions that normally recombine almost exclusively during fetal thymocyte development. The continued rearrangement of the fetal Vgamma3 gene segment in E2A-deficient adult thymocytes correlates with increased levels of Vgamma3 germline transcripts and increased levels of double-stranded DNA breaks at the recombination signal sequence bordering Vgamma3. Additionally, rearrangements to a number of Vgamma and Vdelta gene segments used predominantly during adult development are significantly reduced in E2A-deficient thymocytes. Interestingly, at distinct stages of T lineage development, both the increased and decreased rearrangement of particular Vdelta gene segments is highly sensitive to the dosage of the E2A gene products, suggesting that the concentration of the E2A proteins is rate limiting for the recombination reaction involving these Vdelta regions.

Animals↗
PubMed1998

Gammadelta T cells in host defense and epithelial cell biology.

Recent studies have demonstrated increased numbers of gammadelta T cells in a variety of human infectious as well as noninfectious diseases. In some cases gammadelta T cells could be shown to destroy infected or transformed cells. Advances in the identification of ligands recognized by gammadelta T cells and the development of animal model systems to study these cells in vivo should overcome some of the major obstacles currently preventing a better understanding of gammadelta T cell function in immune responses. As we gain this knowledge it may become possible to design therapeutic strategies exploiting unique properties of gammadelta T cells to promote more effective immunity.

Animals↗
PubMed1997

Thymic cortical epithelium is sufficient for the development of mature T cells in relB-deficient mice.

Thymic development of T lymphocytes progresses as a consequence of both TCR-mediated and non-TCR-mediated interactions between thymocytes and stromal cells. As relB-deficient mice appear to lack thymic medullary epithelium and mature dendritic cells, we studied the effect of this "cortex-only" thymus on T cell development. Two major consequences were observed. First, in both relB mutant and TCR transgenic/relB mutant mice, positive selection of both TCR alpha beta and delta gamma T cells appeared to proceed normally, with export of fully functional T cells to the periphery, suggesting that the thymic medullary stromal cells are not required for full maturation of T cells nor is an organized medullary compartment required for accumulation of mature single positive CD4 and CD8 T cells. Second, thymic negative selection was impaired, as evidenced by significant autoreactive proliferative responses to normal spleen stimulators. Peripheral T cells in relB mutant mice showed an unusually high proportion of CD69+ and CD44high cells. While some of these cells may be autoreactive T cells, most of the cells appeared to be activated by cytokines produced by relB mutant nonlymphoid cells, as the effect is minimized in relB mutant bone marrow chimeras. In sum, while the TCR-mediated steps in T cell maturation require both thymic cortex and medulla (epithelium and dendritic cells) for normal positive and negative selection of the repertoire, non-TCR-mediated interactions in the thymic cortex alone are sufficient to generate mature functional T cells.

Animals↗
PubMed1997

An innate view of gamma delta T cells.

Findings made during the past few years demonstrate that gamma delta T cells apparently share with macrophages a propensity to recognize nonpeptidic molecules of the kind most commonly associated with microorganisms and stressed cells. In general, recognition of these antigens by gamma delta T cells involves the antigen receptor but does not require antigen presenting cells to express MHC gene products or to have a functional antigen processing machinery. Other recent advances continue to support the notion that gamma delta T cells can perform specialized functions related to the repair of tissue damage.

Animals↗
PubMed1997

Integrin alpha 6A beta 1 induces CD81-dependent cell motility without engaging the extracellular matrix migration substrate.

It is well established that integrins and extracellular matrix (ECM) play key roles in cell migration, but the underlying mechanisms are poorly defined. We describe a novel mechanism whereby the integrin alpha 6 beta 1, a laminin receptor, can affect cell motility and induce migration onto ECM substrates with which it is not engaged. By using DNA-mediated gene transfer, we expressed the human integrin subunit alpha 6A in murine embryonic stem (ES) cells. ES cells expressing alpha 6A (ES6A) at the surface dimerized with endogenous beta 1, extended numerous filopodia and lamellipodia, and were intensely migratory in haptotactic assays on laminin (LN)-1. Transfected alpha 6A was responsible for these effects, because cells transfected with control vector or alpha 6B, a cytoplasmic domain alpha 6 isoform, displayed compact morphology and no migration, like wild-type ES cells. The ES6A migratory phenotype persisted on fibronectin (Fn) and Ln-5. Adhesion inhibition assays indicated that alpha 6 beta 1 did not contribute detectably to adhesion to these substrates in ES cells. However, anti-alpha 6 antibodies completely blocked migration of ES6A cells on Fn or Ln-5. Control experiments with monensin and anti-ECM antibodies indicated that this inhibition could not be explained by deposition of an alpha 6 beta 1 ligand (e.g., Ln-1) by ES cells. Cross-linking with secondary antibody overcame the inhibitory effect of anti-alpha 6 antibodies, restoring migration or filopodia extension on Fn and Ln-5. Thus, to induce migration in ES cells, alpha 6A beta 1 did not have to engage with an ECM ligand but likely participated in molecular interactions sensitive to anti-alpha 6 beta 1 antibody and mimicked by cross-linking. Antibodies to the tetraspanin CD81 inhibited alpha 6A beta 1-induced migration but had no effect on ES cell adhesion. It is known that CD81 is physically associated with alpha 6 beta 1, therefore our results suggest a mechanism by which interactions between alpha 6A beta 1 and CD81 may up-regulate cell motility, affecting migration mediated by other integrins.

Amino Acid Sequence↗
PubMed1996

Chemokine expression by intraepithelial gamma delta T cells. Implications for the recruitment of inflammatory cells to damaged epithelia.

T cells expressing gamma delta TCR may have evolved to recognize Ag in a different manner as well as perform a broader set of functions than T cells with alpha beta TCR. In this study, we tested the hypothesis that dendritic epidermal T cells (DETC) bearing the invariant V gamma 3V delta 1 TCR may be able to signal the migration of peripheral alpha beta T cells to the epidermis by secreting specific chemokines. Expression of macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, RANTES, and lymphotactin was inducible in DETC 7-17 cells, whereas mRNA for monocyte chemoattractant protein (MCP)-1 could not be detected. Strikingly, lymphotactin was the most abundant chemokine produced by activated DETC 7-17 cells. Activated primary DETC cultures also produced copious amounts of lymphotactin mRNA. Similarly, freshly isolated and activated intestinal intraepithelial T cells (i-IEL) with gamma delta TCR expressed high levels of lymphotactin mRNA. In contrast, lymphotactin mRNA was present in activated spleen gamma delta T cells at low basal levels. Migration of CD8+ T cells induced by culture supernatants from stimulated DETC 7-17 cells was strongly reduced in the presence of a neutralizing anti-lymphotactin antiserum and to a lesser extent by neutralizing anti-MIP-1 alpha, anti-MIP-1 beta, or anti-RANTES antiserum. The presence of lymphotactin in supernatants from activated DETC 7-17 cultures was directly demonstrated by Western blot analysis. These observations are consistent with a model in which gamma delta IEL play an active multi-faceted role in the maintenance of epithelia homeostasis.

Animals↗
PubMed1996

A role for CD81 in early T cell development.

Early stages of T cell development are thought to include a series of coordinated interactions between thymocytes and other cells of the thymus. A monoclonal antibody specific for mouse CD81 was identified that blocked the appearance of alpha beta but not gamma delta T cells in fetal organ cultures initiated with day 14.5 thymus lobes. In reaggregation cultures with CD81-transfected fibroblasts, CD4-CD8- thymocytes differentiated into CD4+CD8+ T cells. Thus, interactions between immature thymocytes and stromal cells expressing CD81 are required and may be sufficient to induce early events associated with T cell development.

Amino Acid Sequence↗
PubMed1996

Molecular and cellular biology of dendritic epidermal T cells.

The function and specificity of gamma delta T cells remain enigmatic. Dendritic epidermal T cells (DETC) expressing an invariant gamma delta TCR represent a well established model system to investigate these key issues. Accumulating evidence supports the initial observation that recognition of a keratinocyte self-antigen by DETC proceeds without a requirement for MHC gene products. In addition, recent data have identified bioactive polypeptides expressed by DETC but not by most other T cells. For example, keratinocyte growth factor appears to be exclusively produced by activated DETC and intestinal intraepithelial gamma delta cells. These findings suggest that DETC may recognize antigen in novel ways as well as perform specialized functions complementary to those normally attributed to T cells.

Animals↗
PubMed1994

Modulation of epithelial cell growth by intraepithelial gamma delta T cells.

The role played in immune surveillance by gamma delta T cells residing in various epithelia has not been clear. It is shown here that activated gamma delta T cells obtained from skin and intestine express the epithelial cell mitogen keratinocyte growth factor (KGF). In contrast, intraepithelial alpha beta T cells, as well as all lymphoid alpha beta and gamma delta T cell populations tested, did not produce KGF or promote the growth of cultured epithelial cells. These results suggest that intraepithelial gamma delta T cells function in surveillance and in repair of damaged epithelial tissues.

Animals↗
PubMed1994

Developmental expression of the alpha IEL beta 7 integrin on T cell receptor gamma delta and T cell receptor alpha beta T cells.

A novel monoclonal antibody, 2E7, was shown by immunoprecipitation to be reactive with the alpha IEL beta 7 integrin and was employed to analyze the expression of this integrin in lymphocyte subsets and during T cell ontogeny. In adult lymph nodes, alpha IEL was expressed at low levels by 40-70% of CD8+ T cells and < 5% of CD4+ T cells. However, virtually all intestinal intraepithelial lymphocytes and approximately 20% of lamina propria CD4+ T cells were 2E7+, indicating a preferential expression of this integrin on mucosal T cells. Examination of alpha IEL integrin expression during thymus ontogeny revealed that approximately 3-5% of fetal or adult thymocytes were 2E7+. Interestingly, early in fetal thymus ontogeny, approximately 40% of 2E7+ cells expressed T cell receptor (TcR)-gamma delta and this subset persisted through birth. A developmental switch occurred such that 2E7+ TcR- CD4-8+ cells detected on fetal day 19 were followed by 2E7+ TcR-alpha beta CD4-8+ cells in the neonatal thymus. The latter population persisted throughout thymus ontogeny into adulthood. Interestingly, a subset of TcR-gamma delta V gamma 3+ day 16 fetal thymocyte dendritic epidermal cell (DEC) precursors were 2E7+, but all mature DEC expressed high levels of alpha IEL integrin, suggesting that the alpha IEL integrin was acquired late in DEC maturation. This possibility was strengthened by immunohistochemical localization of the majority of 2E7+ gamma delta and alpha beta T cells to the medullary regions of the thymus. Overall, the results demonstrate a developmentally ordered expression pattern of the alpha IEL beta 7 integrin that suggests a common function for this integrin during TcR-gamma delta and -alpha beta CD4-8+ T cell thymocyte development or perhaps in effector functions for these subsets.

Animals↗
PubMed1994

Activation and function of gamma delta T cells.

T-cell receptor gene rearrangements in gamma delta T cells have been the subject of intense molecular investigations. This year, much has been learned about the mechanisms controlling this process. However, the specificity and function of gamma delta T cells still remains enigmatic. The application of molecular technology including the availability of mutant mice lacking defined T-cell populations and immunologically relevant surface proteins is beginning to provide answers as well as some surprises.

Animals↗
PubMed1991

Recognition of self antigens by skin-derived T cells with invariant gamma delta antigen receptors.

Thy-1+ dendritic epidermal T cells (dECs) express invariant gamma delta antigen receptors and are found in intimate contact with keratinocytes in murine epidermis--thus raising the possibility that keratinocytes express a ligand for the antigen receptor of these T cells. Thy-1+ dECs were stimulated to produce lymphokines by interaction with keratinocytes in vitro. This stimulation was mediated through the dEC antigen receptor and did not appear to be restricted by the major histocompatibility complex. Thus, dECs can recognize self antigens and may participate in immune surveillance for cellular damage rather than for foreign antigens.

Animals↗
PubMed1991

Gamma delta T cells in murine epithelia: origin, repertoire, and function.

The earliest TCR+ cells to appear during fetal development express products of the gamma and delta loci, and emerge as successive waves of cells bearing different V gamma gene products. These appear to emigrate and seed different epithelia. The TCR repertoire of the first two of these waves, V gamma 3 and V gamma 4, respectively, is extremely restricted. Whether the repertoire of these cells is restricted by selective processes or is shaped by developmental restrictions on rearrangements remains to be determined. These cells may function in surveillance for signals of trauma by recognizing self products induced by cellular stress.

Animals↗
PubMed1991

The immunobiology of T cells with invariant gamma delta antigen receptors.

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.

Amino Acid Sequence↗
PubMed1991

Murine T cells with invariant gamma delta antigen receptors: origin, repertoire, and specificity.

T cells bearing invariant gamma delta T cell antigen receptors localize to distinct epithelial sites in the adult mouse. These gamma delta T cells differ from the lymphoid alpha beta and gamma delta T cells in several ways. The epithelial gamma delta T cells appear to be the product of the earliest waves of TCR expressing cells in the fetal thymus. Additionally, the rearranged TCR junctions exhibit a distinct lack of diversity, possibly a result of the fetal origin and a specialized selection process. The use of a single invariant TCR and strict tissue localization suggest that these gamma delta T cells may provide a specialized function in the epithelial tissues distinct from that of the circulating alpha beta and gamma delta T cells.

Animals↗
PubMed1990

Origin of Thy-1+ dendritic epidermal cells of adult mice from fetal thymic precursors.

The skin of mice contains dendritic epidermal cells carrying the Thy-1 antigen (Thy-1+ dEC) which express antigen receptors composed of the T-cell antigen receptor (TCR) gamma- and delta-chains. Although the role of the thymus in the generation of most T cells is well established, the involvement of the thymus in the generation of Thy-1+ dEC is not clear. Because bone marrow cells can give rise in Thy-1+ dEC in chimaeric mice and Thy-1+ dEC are detected in the skin of athymic nude nice, it has been proposed that Thy-1+ dEC arise continuously from bone marrow precursors by a thymus-independent mechanism. But it has recently been determined that Thy-1+ dEC in nude mice do not express TCR at the cell surface, and that the gamma- and delta-chain genes are in germ-line configuration, leaving the role of the thymus in the generation of Thy-1+ dEC uncertain. Most Thy-1+ dEC in all normal mouse strains examined express TCR containing the V gamma 3 gene product. This V gene segment is expressed on the first wave of TCR-expressing cells to emerge during fetal development, and in adult mice is detectable only on cells in the epidermis. In addition to use of this 'fetal' V gamma segment, other features of the Thy-1+ dEC TCR genes, including absence or minimal presence of nongerm-line-encoded nucleotides at the junctions and use of a single D element in the rearranged delta-chain gene are typical of rearrangements found in fetal, and not adult, thymus. Here we demonstrate that precursors that are present only in the fetal thymus give rise to Thy-1+ dEC in the skin of adult mice.

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