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M Kronenberg

Publications and source records attributed to M Kronenberg.

At least 19 recordsLinked to original sources
PubMed1996

TAP-independent selection of CD8+ intestinal intraepithelial lymphocytes.

Intestinal intraepithelial lymphocytes (IEL) are mostly CD8 single positive T cells. IEL with a TCR-alpha(beta) that are CD8 single positive are absent from beta(2)-microglobulin (beta(2)m)-deficient mice, consistent with the idea that these IEL, like other TCR-alpha(beta)+, CD8+ T cells, require class I molecules for positive selection. In contrast, here we show that substantial numbers of TCR-alpha(beta)+, CD8 single positive IEL are present in mice deficient for the transporter associated with Ag processing 1 (TAP 1) gene, although T cells with this phenotype are absent from thymus, spleen, and lymph nodes of these same mice. The majority of TCR-alpha(beta)+, CD8 single positive IEL in TAP-deficient mice expresses CD8 molecules composed of alpha(alpha) homodimers and they express a diverse set of V(beta) gene segments. In addition, the number of TCR-alpha(beta)+, CD4/CD8 double positive IEL is decreased in beta(2)m-deficient mice but not in TAP-deficient mice. The dependence of the two TCR-alpha(beta)+ IEL populations that express CD8alpha(alpha) homodimers on beta(2)m as opposed to TAP molecules is striking. It suggests that TAP-independent but beta(2)m-requiring nonclassical class I molecules expressed by cells in the intestine, such as the thymus leukemia Ag and CD1, could play a pivotal role in the development and/or the accumulation of major subpopulations of TCR-alpha(beta)+ IEL.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Antigen-presenting function of the mouse CD1 molecule.

CD1 molecules are distantly related to major histocompatibility complex (MHC)-encoded class I molecules, and they are coexpressed with beta2 microglobulin (beta2m). In the mouse, CD1 is expressed by intestinal epithelial cells and also by some cells in spleen and lymph node. We have shown that surface expression of mouse CD1 (mCD1) is not dependent upon a functional transporter associated with antigen processing (TAP). This, and other data, suggest that mCD1 may acquire peptides in an intracellular compartment other than the endoplasmic reticulum, where classical class I molecules bind peptide. mCD1 molecules also are distinct from classical class I molecules with regard to the types of peptides that they bind. We have demonstrated that mCD1 molecules preferentially bind peptides much longer than the 8-9 amino acids typical of the peptides that bind to classical class I molecules. The sequence motif for mCD1 peptide binding is characterized by the presence of bulky and hydrophobic amino acid side chains. We have generated mCD1-restricted and peptide-specific T-cell lines, thereby demonstrating the immunologic relevance of peptide binding to mCD1. The reactive T cells are TCR alphabeta+ and CD8+, a phenotype typical of many lymphocytes in both lymph node and intestinal mucosae. We speculate that mCD1 molecules may be capable of sampling peptides from the gut lumen and presenting them to mucosal T lymphocytes. In this way, they may function in the maintenance of normal mucosal homeostasis, and perhaps also in the induction of systemic tolerance to antigens delivered by the oral route. In summary, CD1 molecules are a novel category of antigen-presenting molecules that have features in common with class I molecules, features in common with class II, and properties distinct from either subset of antigen-presenting molecules. Further studies of the antigen-presenting function of these molecules are certain to yield new insight into immune regulation and perhaps also into the mechanism of oral tolerance.

Administration, Oral↗
PubMed1996

Intestinal intraepithelial lymphocytes respond to systemic lymphocytic choriomeningitis virus infection.

Intestinal intraepithelial lymphocytes (IEL) are a population of cells consisting mostly of CD8+ T lymphocytes. Although their function is unknown, because of their location within the epithelium it has been postulated that IEL may be involved in defense against infection of the gut mucosa by pathogens including viruses. To address this issue, we have examined IEL populations from BALB/c mice systemically infected with lymphocytic choriomeningitis virus (LCMV). Viral infection induced a virus-specific cytotoxic response by IEL at 8 days postinfection. This virus-specific cytotoxic T lymphocyte (CTL) response was MHC class I restricted, and as is true for splenic T cells, recognition of viral antigen occurred predominantly in the context of the Ld molecule. The effector cells could be depleted by treatment with anti-CD8 antibody plus complement. In vivo treatment of mice with anti-alpha beta T cell receptor (TCR) antibody during the course of viral infection abrogated the response, suggesting that the virus-specific CTL were cells that express the alpha beta rather than gamma delta TCR. Consistent with this, no virus-specific IEL response could be detected in athymic mice, which have TCR gamma delta+ but not TCR alpha beta+ IEL. LCMV antigen could not be detected in the epithelium of the intestine, suggesting that viral antigen may have been encountered elsewhere. These data demonstrate for the first time a specific response by IEL to virus given by a non-oral route, and they suggest that thymus-derived alpha beta T cells can migrate to the intestinal epithelium following activation, where they may play a role in the response to virus and perhaps other infections.

Animals↗
PubMed1995

CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice.

Rather unexpectedly, major histocompatibility complex class II-deficient mice have a significant population of peripheral CD4+ T lymphocytes. We have investigated these cells at the population and clonal levels. CD4+ T lymphocytes from class II-deficient animals are thymically derived, appear early in ontogeny, exhibit the phenotype of resting memory cells, are potentially functional by several criteria, and have a diverse T cell receptor repertoire. They do not include substantially elevated numbers of NK1.1+ cells. Hybridomas derived after polyclonal stimulation of the CD4+ lymphocytes from class II-deficient animals include a subset with an unusual reactivity pattern, responding to splenocytes from many mouse strains including the strain of origin. Most members of this subset recognize the major histocompatibility complex class Ib molecule CD1; their heterogeneous reactivities and T cell receptor usage further suggest the involvement of peptides and/or highly variable posttranslational modifications.

Animals↗
PubMed1995

Peptide binding and presentation by mouse CD1.

CD1 molecules are distantly related to the major histocompatibility complex (MHC) class I proteins. They are of unknown function. Screening random peptide phage display libraries with soluble empty mouse CD1 (mCD1) identified a peptide binding motif. It consists of three anchor positions occupied by aromatic or bulky hydrophobic amino acids. Equilibrium binding studies demonstrated that mCD1 binds peptides containing the appropriate motif with relatively high affinity. However, in contrast to classical MHC class I molecules, strong binding to mCD1 required relatively long peptides. Peptide-specific, mCD1-restricted T cell responses can be raised, which suggests that the findings are of immunological significance.

Amino Acid Sequence↗
PubMed1995

CD1-restricted T cell recognition of microbial lipoglycan antigens.

It has long been the paradigm that T cells recognize peptide antigens presented by major histocompatibility complex (MHC) molecules. However, nonpeptide antigens can be presented to T cells by human CD1b molecules, which are not encoded by the MHC. A major class of microbial antigens associated with pathogenicity are lipoglycans. It is shown here that human CD1b presents the defined mycobacterial lipoglycan lipoarabinomannan (LAM) to alpha beta T cell receptor-bearing lymphocytes. Presentation of these lipoglycan antigens required internalization and endosomal acidification. The T cell recognition required mannosides with alpha(1-->2) linkages and a phosphotidylinositol unit. T cells activated by LAM produced interferon gamma and were cytolytic. Thus, an important class of microbial molecules, the lipoglycans, is a part of the universe of foreign antigens recognized by human T cells.

Antigen Presentation↗
PubMed1995

Spontaneous resistance to acute T-cell leukaemias in TCRV gamma 1.1J gamma 4C gamma 4 transgenic mice.

The concept of tumour surveillance implies that specific and non-specific components of the immune system eliminate tumours in the early phase of malignancy. The immunological mechanisms that control growth of preneoplastic cells are, however, not known. T cells expressing gamma delta T-cell receptors (TCR) were first described as lymphocytes with reactivity against various tumour cells, which suggests that gamma delta T cells could mediate tumour surveillance. Here we show that TCRV gamma 1.1J gamma 4C gamma 4 transgenic mice are spontaneously resistant to acute T-cell leukaemias but cannot reject non-haematopoietic tumours. TCRV gamma 1.1J gamma 4C gamma 4+ hybridomas isolated from these mice react in vitro against almost all haematopoietic tumour cell lines tested. Recognition of tumour cells depends on the gamma delta TCR but is independent of major histocompatibility complex (MHC) class I, MHC class II, or TAP-2 peptide transporter expression. Ligand recognition is influenced by the murine Nromp gene, which confers resistance or susceptibility to tuberculosis, lepra and leishmaniasis. These data indicate that TCRV gamma 1.1+ T cells confer spontaneous immunity against haematopoietic tumours in vivo and link innate resistance to bacterial infections with tissue-specific tumour surveillance by gamma delta+ T cells.

3T3 Cells↗
PubMed1995

Nonclassical behavior of the thymus leukemia antigen: peptide transporter-independent expression of a nonclassical class I molecule.

The thymus leukemia (TL) antigen is a major histocompatibility complex-encoded nonclassical class I molecule. Here we present data demonstrating that expression of the TL antigen, unlike other class I molecules, is completely independent of the function of the transporter associated with antigen processing (TAP). The TL antigen is expressed by transfected TAP-2-deficient RMA-S cells when these cells are grown at 37 degrees C. In transfected RMA cells, the kinetics of arrival of TL antigen on the cell surface are similar to those of a classical class I molecule. The kinetics are not altered in TAP-deficient RMA-S cells, demonstrating that surface TL expression in TAP-deficient cells is not due to the stable expression of a few molecules that leak out by a TAP-independent pathway. Soluble TL molecules produced by Drosophila melanogaster cells are highly resistant to thermal denaturation, unlike peptide-free classical class I molecules synthesized by these insect cells. In addition, these soluble TL molecules are devoid of detectable bound peptides. The results demonstrate that the TL antigen is capable of reaching the surface without bound peptide, although acquisition of peptide or some other ligand through a TAP-independent pathway cannot be formally excluded. We speculate that the ability of the TL antigen to reach the cell surface, under conditions in which other class I molecules do not, may be related to a specialized function of the TL molecule in the mucosal immune system, and possibly in the stimulation of intestinal gamma delta T cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Organization of the V gene segments in mouse T-cell antigen receptor alpha/delta locus.

The mouse T-cell receptor (TCR) alpha/delta locus was mapped using 17 V alpha and 4 V beta subfamily-specific probes. Four complementary methods were used: (1) an estimate of the V gene repertoire by Southern blot analysis of genomic DNA with subfamily-specific probes; (2) an analysis of V gene segments deleted by TCR gene rearrangements from a panel of T-cell tumors and hybridomas; (3) an analysis of overlapping clusters of cosmid clones; and (4) an analysis of large DNA fragments separated by field-inversion gel electrophoresis. The alpha/delta locus spans about 1 Mb. The distance between the 3'-most V gene segment (V delta 1) and the delta constant gene (C delta) is no more than 150 kb. Sixty-six V gene segments have been mapped physically on cosmids. The members of individual V alpha gene segment subfamilies are dispersed throughout the locus. In contrast, the V delta gene segments V delta 1 to 5 are clustered at the 3' end of the V gene segment cluster. At least two DNA segment duplications, 45 to 80 kb in length, are present in the locus. These data provide information on the evolution of the alpha/delta locus and on organization features that might influence the expression of specific V gene segments in gamma delta cells.

Animals↗
PubMed1994

Antigens recognized by gamma delta T cells.

Recent evidence demonstrates the important role played by gamma delta T cells in resistance to infections. Despite this, in most cases the antigens recognized by the responding gamma delta T cells are unknown. Antigen recognition by some gamma delta T-cell populations may not require the participation of either MHC class I or class II molecules. In other cases, evidence exists for the participation of MHC-encoded molecules, particularly non-classical class I molecules.

Animals↗
PubMed1994

A unique pattern of lymphokine synthesis is a characteristic of certain antigen-specific suppressor T cell clones.

We report that the lymphokines (IFN-gamma) and IL-10 are co-synthesized by previously described CD3+ TCR alpha beta+, minor antigen-specific suppressor T cell clones. IFN-gamma and IL-10 are known to (i) be characteristically produced by different helper T cell types, Th1 and Th2 respectively, and (ii) inhibit the function of the reciprocal subset of T cells: IFN-gamma inhibits the function of Th2 and IL-10 that of Th1 cells. Although Th0 cells are also known to synthesize cytokines of both the Th1- and Th2-type T cells, the suppressor T cells described in this report are different from Th0 cells in that they produce (i) neither IL-2 nor IL-4 molecules and (ii) stimulation via their CD3-TCR system seems independent of both IL-2 and IL-4, the typical autocrine molecules for T cell proliferation. The lymphokine profile of these suppressor T (Ts) cell clones, as well as those of human antigen-specific Ts cells reported earlier, suggests that co-synthesis of some Th1-like and some Th2-like cytokines may be a characteristic of antigen-specific Ts cells as opposed to the type of reciprocal inhibition mediated through IFN-gamma or IL-10, which is antigen non-specific.

Animals↗
PubMed1994

Masseter and temporalis surface electromyography in patients wearing complete dentures comparing anterior and posterior occlusal concepts--a pilot study.

The activity of jaw elevator muscles (masseter and anterior temporal muscle) was studied by surface electromyography in 17 patients wearing complete dentures with anterior-canine guidance. Baseline electromyography was recorded with the dentures and compared to recordings obtained with two different splints adapted to the upper denture, one providing anterior guidance leading to immediate disclusion of the posterior teeth during any jaw movement, the other providing posterior guidance buccally on the working side and lingually on the non-working side (bilaterally balanced occlusion). Recordings were obtained during a sequence of different jaw movements: postural position, maximal tooth contact in intercuspal position, protrusive movement of the mandible (under tooth contact) and during lateral excursions, also carried out under tooth contact. Muscle activity was not significantly different as recorded with dentures only versus with the splints providing anterior guidance. However, a significant increase in activity was observed with bilaterally balanced occlusion. The results of this study in edentulous people are similar to those found in patients with natural teeth.

Aged↗
PubMed1994

Mouse T lymphocytes that express a gamma delta T-cell antigen receptor contribute to resistance to Salmonella infection in vivo.

Mice depleted of lymphocytes expressing the alpha beta or the gamma delta T-cell receptor for antigen (TCR) by antibody treatment were infected orally with Salmonella enteritidis. In both groups of treated mice, the 50% lethal dose decreased, suggesting that both the alpha beta TCR+ and the gamma delta TCR+ subsets contribute to resistance to oral infection. These data provide further evidence for the contribution of gamma delta T cells in the response to bacterial infections.

Animals↗
PubMed1994

Tolerance and self-reactivity in V gamma 1.1C gamma 4 transgenic mice.

Immunological tolerance is the process of inhibiting or eliminating lymphocytes that recognize self-derived antigens. By removing potentially harmful self-reactive clones, this mechanism allows for the random generation of a diverse repertoire of T-cells capable of responding to foreign pathogens. Although all self-reactive T-cells should be removed from the repertoire, it is quite clear from many recent studies that a significant fraction of T-cells bearing gamma delta T-cell receptors (TCR) recognize self-derived antigens in normal healthy mice. The presence of self-reactive T-cells in healthy animals presents a paradox which may be explained by understanding the transient expression of the antigens (e.g., MHC class Ib, Heat Shock Proteins) that have been identified for gamma delta T-cells thus far. Data from experiments with V gamma 1.1C gamma 4 transgenic mice demonstrating the presence of self-reactive gamma delta T-cells and their influence on lymphoid development and immune surveillance will be examined in this review.

Animals↗
PubMed1994

Structure and function of H-2 T (Tla) region class I MHC molecules.

The T region of the mouse major histocompatibility complex (MHC) encodes a relatively large number of nonclassical or nonpolymorphic class I genes. In BALB/c mice, at least five of these genes are likely to encode a functional class I gene product. Some of these T region products are ubiquitously expressed, while others are expressed by just a few tissues. In the second category, the thymus leukemia (TL) antigen, which is encoded in the T region by T3 and T18 genes, is expressed primarily by intestinal epithelial cells and thymocytes. Inspection of the sequences of the alpha 1 and alpha 2 domains, which could encode a peptide binding site in these molecules, indicates that in several cases conserved amino acids important for peptide binding by classical class I molecules are present, suggesting that these nonclassical class I molecules can bind nonamer peptides. On the other hand, analysis of the sequence of the T10d gene product suggests that it can not bind nonamer peptides in a fashion similar to classical class I molecules. Although there are so far no examples of the recognition of defined peptides in the context of T region gene products, there are several examples of T cell recognition of these class I molecules. Both alpha beta and gamma delta T cell receptors are involved in this recognition. Transgenic mice that over express the TL antigen show a variety of abnormalities in thymocyte differentiation and function, providing some support for the hypothesis that this nonclassical class I molecule plays a role in T-cell differentiation. Despite this, the most likely function for T region encoded and other nonclassical class I gene products is a specialized antigen presenting function, perhaps in restricted anatomic sites or to specialized T-cell populations.

Amino Acid Sequence↗
PubMed1993

The alpha 3 domain of the Qa-2 molecule is defective for CD8 binding and cytotoxic T lymphocyte activation.

Qa-2 is a nonclassical class I molecule encoded by the Q7 gene within the mouse major histocompatibility complex (MHC). Results from previous experiments on Qa-2, and on a chimeric Ld molecule (LQ3) in which the alpha 3 domain is encoded by Q7b, suggested that the alpha 3 domain of Qa-2 does not carry out the functions typical of the alpha 3 domains in other classical and nonclassical class I antigens. Class I molecules that contain the Qa-2 alpha 3 domain are poorly recognized by primary cytotoxic T lymphocytes (CTLs), and do not function normally in either positive or negative selection in vivo. By employing a cell-cell adhesion assay we demonstrate directly that the Qa-2 alpha 3 domain in the context of the LQ3 hybrid molecule cannot bind to human CD8, although other mouse class I alpha 3 domains bind efficiently. In addition, CD8-dependent CTL-mediated lysis of target cells, in a system which requires mouse CD8-class I alpha 3 domain interactions, is deficient in cells that express the Qa-2 alpha 3 domain. When combined with our earlier work on LQ3 transgenic mice, these results provide additional molecular support for the hypothesis that interaction with CD8 is required for both positive and negative selection of class I restricted T cells in the thymus. As the Qa-2 alpha 3 domain sequence does not differ from the previously defined minimal CD8 binding sequence of other class I molecules, these results also suggest that additional amino acids in the alpha 3 domain must be critical for CD8 binding and CTL activation.

Amino Acid Sequence↗