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S A Porcelli

Publications and source records attributed to S A Porcelli.

67 records · Page 4Linked to original sources
PubMed1996

Cytoplasmic tail-dependent localization of CD1b antigen-presenting molecules to MIICs.

CD1 proteins have been implicated as antigen-presenting molecules for T cell-mediated immune responses, but their intracellular localization and trafficking remain uncharacterized. CD1b, a member of this family that presents microbial lipid antigens of exogenous origin, was found to localize to endocytic compartments that included the same specialized subset of endosomes in which major histocompatibility complex (MHC) class II molecules are proposed to bind endocytosed antigens. Unlike MHC class II molecules, which traffic to antigen-loading endosomal compartments [MHC class II compartments (MIICs)] primarily as a consequence of their association with the invariant chain, localization of CD1b to these compartments was dependent on a tyrosine-based motif in its own cytoplasmic tail.

Amino Acid Sequence↗
PubMed1996

T-cell recognition of non-peptide antigens.

Studies of two distinct human T-cell systems have provided the exciting finding that T cells are able to recognize non-peptide antigens: gammadelta T cells have been shown to recognize isopentenyl pyrophosphate and related structures and human CD1 has been shown to present microbial lipids and lipoglycans such as mycolic acids and lipoarabinomannan to T cells. T-cell responses to these non-peptide antigens should provide a strategic target for immunologic intervention in infectious disease.

Antigen Presentation↗
PubMed1996

Antigen presentation by CD1 and MHC-encoded class I-like molecules.

Three known lineages of antigen-presenting molecules restrict T-cell responses to microbial antigens: MHC class I and MHC encoded class I like molecules present peptides derived from the proteolysis of intracellular pathogens, MHC class ii molecules present peptides derived from the proteolysis of extracellular pathogens and CD1 molecules present unique microbial lipids and glycolipids. Recent studies have indicated that CD1 molecules mediate a novel system of antigen presentation and that MHC-encoded class I-like molecules can present unique subsets of intracellularly derived peptides.

Animals↗
PubMed1995

A pathway of costimulation that prevents anergy in CD28- T cells: B7-independent costimulation of CD1-restricted T cells.

A class of molecules that is expressed on antigen presenting cells, exemplified by CD80 (B7), has been found to provide a necessary costimulatory signal for T cell activation and proliferation. CD28 and CTLA4 are the B7 counterreceptors and are expressed on the majority of human CD4+ T cells and many CD8+ T cells. The signal these molecules mediate is distinguished from other costimulatory signals by the finding that T cell recognition of antigen results in a prolonged state of T cell unresponsiveness or anergy, unless these costimulatory molecules are engaged. However, nearly half of the CD8+ and CD4-CD8- T cells lack CD28, and the costimulatory signals required for the activation of such cells are unknown. To understand the pathways of activation used by CD28- T cells, we have examined the costimulatory requirements of antigen-specific CD4-CD8- TCR(+)-alpha/beta circulating T cells that lack the expression of CD28. We have characterized two T cell lines, DN1 and DN6, that recognize a mycobacterial antigen, and are restricted not by major histocompatibility complex class I or II, but by CD1b or CD1c, two members of a family of major histocompatibility complex-related molecules that have been recently implicated in a distinct pathway for antigen presentation. Comparison of antigen-specific cytolytic responses of the DN1 and DN6 T cell lines against antigen-pulsed CD1+ monocytes or CD1+ B lymphoblastoid cell lines (B-LCL) demonstrated that these T cells recognized antigen presented by both types of cells. However, T cell proliferation occurred only when antigen was presented by CD1+ monocytes, indicating that the CD1+ monocytes expressed a costimulatory molecule that the B-LCL transfectants lacked. This hypothesis was confirmed by demonstrating that the T cells became anergic when incubated with the CD1(+)-transfected B-LCL in the presence of antigen, but not in the absence of antigen. The required costimulatory signal occurred by a CD28-independent mechanism since both the CD1+ monocytes and CD1+ B-LCL transfectants expressed B7-1 and B7-2, and DN1 and DN6 lacked surface expression of CD28. We propose that these data define a previously unrecognized pathway of costimulation for T cells distinct from that involving CD28 and its counterreceptors. We suggest that this B7-independent pathway plays a crucial role in the activation and maintenance of tolerance of at least a subset of CD28- T cells.

Antigen-Presenting Cells↗
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

Structure and function of the CD1 family of MHC-like cell surface proteins.

The CD1 family of proteins are structurally related to MHC class I proteins, but are only distantly related to the class I proteins or other MHC-linked class I-like proteins. Sequence comparisons indicate that the CD1 proteins have evolved into two subfamilies, those which are similar to human CD1a, b, and c and those which are similar to human CD1d. The CD1A-, B-, and C-like genes were deleted from rodents and the CD1D gene was duplicated. CD1a, b, and c are expressed by thymocytes, dendritic cells, activated monocytes, and B cells (CD1c), a tissue distribution which strongly suggests a role in antigen presentation. In contrast, CD1d and its murine homologues are expressed by many cells outside of the lymphoid and myeloid lineages. The CD1 proteins are in most cases expressed as beta 2mg-associated membrane glycoproteins, but may associate with additional proteins. CD1d is expressed on the surface of intestinal epithelial cells in a nonglycosylvated form without beta 2mg. Whether the CD1 proteins function as antigen-presenting molecules is unresolved, but it is unlikely that they present conventional peptide antigens. Strong evidence indicates that murine CD1 proteins are recognized by a population of NK1.1+, CD4+ or CD4-CD8- (double negative, DN) T cells which express an invariant TCR alpha chain. CD1d is most likely recognized by the homologous T cell population in humans. DN alpha beta T cells which recognize CD1a, b, or c have been isolated, including clones which recognize a lipid antigen from mycobacteria presented by CD1b. A third potential population of CD1 reactive cells are CD8+ T cells in the intestinal epithelium. Taken together, these observations indicate that CD1 proteins interact with several specialized populations of T cells. The precise biological functions mediated through these interactions remain to be determined.

Amino Acid Sequence↗
PubMed1994

Recognition of a lipid antigen by CD1-restricted alpha beta+ T cells.

Major histocompatibility complex (MHC) class I and class II molecules bind immunogenic peptides and present them to lymphocytes bearing the alpha beta T-cell antigen receptor (TCR). An analogous antigen-presenting function also has been proposed for the non-MHC-encoded CD1 molecules, a family of non-polymorphic, beta 2-microglobulin-associated glycoproteins expressed on most professional antigen-presenting cells. In support of this hypothesis, CD1 molecules are recognized by selected CD4-CD8- alpha beta or gamma delta TCR+ T-cell clones, and we have recently shown that CD1 molecules restrict the recognition of foreign microbial antigens by alpha beta TCR+ T cells. But the substantial structural divergence of CD1 from MHC class I and class II molecules, raises the possibility that the antigens presented by the CD1 system may differ fundamentally from those presented by MHC-encoded molecules. Here we report that a purified CD1b-restricted antigen of Mycobacterium tuberculosis presented to alpha beta TCR+ T cells is mycolic acid, a family of alpha-branched, beta-hydroxy, long-chain fatty acids found in mycobacteria. This example of non-protein microbial antigen recognition suggests that alpha beta TCR+ T cells recognize a broader range of antigens than previously appreciated and that at least one member of the CD1 family has evolved the ability to present lipid antigens.

Antigen Presentation↗
PubMed1990

Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire.

The germline repertoire of variable genes for the TCR-gamma/delta is limited. This, together with the availability of several V delta-specific and a C delta-specific mAbs, has made it possible to assess differences in the TCR-gamma/delta repertoire in man. TCR-gamma/delta cells expressing particular V gene segments have been previously shown to be localized in different anatomical sites. In this study, analysis of TCR-gamma/delta V gene segment usage performed on subjects from the time of birth through adulthood revealed striking age-related changes in the TCR-gamma/delta repertoire in peripheral blood. V delta 1+ gamma/delta T cells predominated in thymus as well as in peripheral blood at birth and then persisted as a relatively constant proportion of CD3+ PBL. However, V delta 2+ gamma/delta T cells that constitute a small proportion of the CD3+ cells in thymus and in peripheral blood at birth, then expand and account for the major population of gamma/delta T cells in PBL in adults. No parallel postnatal expansion of V delta 2+ cells in the thymus was observed, even when paired thymus-peripheral blood specimens were obtained on subjects between the ages of 3 d and 8 yr. The subset of V delta 2+ lymphocytes that was expanded in peripheral blood expressed high levels of CD45RO suggesting prior activation of these cells, consistent with the possibility that their expansion might have resulted from exposure to foreign antigens or superantigens. In contrast, V delta 1+ T cells in PBL showed no comparable increase in relative numbers and were either negative or expressed only low levels of CD45RO. Consistent with evidence for extrathymic peripheral expansion of selective TCR-gamma/delta subsets, no link between MHC haplotype and differences in the TCR-gamma/delta V gene usage between individuals was apparent, and identical twins displayed TCR-gamma/delta variable gene segment phenotypes that were strikingly different from one another. The elements that determine the TCR-gamma/delta repertoire in individuals are not known. It is possible that both thymic selection and extrathymic factors may influence the peripheral repertoire. Recently, TCR-gamma/delta+ lymphocytes have been shown to expand markedly in peripheral lymphoid tissues and infectious lesions in response to mycobacterial antigens, and a correlation between mycobacterial responses and TCR-gamma/delta V gene usage has been shown in mice. The data presented here demonstrated peripheral age-related changes in the gamma/delta repertoire and point to the importance of extrathymic expansion of specific gamma/delta subsets in generating the human TCR-gamma/delta repertoire.

Adult↗