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Fabio R Santori

Publications and source records attributed to Fabio R Santori.

13 recordsLinked to original sources
PubMed2005

Self-peptide/MHC and TCR antagonism: physiological role and therapeutic potential.

TCR antagonists are peptides that bind MHC molecules and can specifically inhibit T cell activation induced by antigens. Studying TCR antagonism has taken an important place in immunology for both theoretical and practical reasons. Deciphering the mechanism(s) of action of TCR antagonists can yield important information about interactions of the TCR with ligands, T cell development, and TCR signaling. Moreover, microorganisms may employ TCR antagonism to elude the attention of the immune system. Finally, specificity of inhibition makes TCR antagonists an ideal tool to seek antigen-specific immunomodulation. Present state of knowledge on these topics is reviewed.

Animals↗
PubMed2004

Select forms of tumor cell apoptosis induce dendritic cell maturation.

Dendritic cells (DC) play a crucial role in initiating immune responses to tumors. DC can efficiently present antigens from apoptotic tumor cells, but apoptotic cells are thought to lack the inflammatory signals required to induce DC maturation. Here, we show that apoptosis of 67NR mouse carcinoma cells via the Fas (CD95) pathway or induced by the anticancer drug bortezomib (PS-341) but not by ultraviolet irradiation is associated with the production of maturation signals for DC. These data have important implications for the effects of chemotherapy on antitumor immunity in solid and hematologic malignancies.

Animals↗
PubMed2004

Delineation of signals required for thymocyte positive selection.

Peptide/MHC complexes capable of inducing positive selection in mouse fetal thymic organ cultures fail to do so in suspension culture. Furthermore, this type of culture does not promote initial stages of differentiation, such as coreceptor down-modulation, unless peptides used for stimulation have (at least) weak agonist activity. We show in this study that signals provided in suspension culture by nonagonist peptide/MHC complexes on the surface of macrophages, even though apparently silent, are sufficient to promote complete phenotypic differentiation when CD4+CD8+ thymocytes are subsequently placed in a proper anatomical setting. Furthermore, the synergistic actions of suboptimal concentrations of phorbol esters and nonagonist peptide/MHC complexes can make the initial stages of positive selection visible, without converting maturation into negative selection. Thus, the correlation between efficiency of positive selection and the degree of coreceptor down-modulation on CD4+CD8+ thymocytes is not linear. Furthermore, these results suggest that the unique role of thymic stromal cells in positive selection is related not to presentation of self-peptide/MHC complexes, but most likely to another ligand.

Animals↗
PubMed2004

Distinct footprints of TCR engagement with highly homologous ligands.

T cell receptor engagement promotes proliferation, differentiation, survival, or death of T lymphocytes. The affinity/avidity of the TCR ligand and the maturational stage of the T cell are thought to be principal determinants of the outcome of TCR engagement. We demonstrate in this study that the same mouse TCR preferentially uses distinct residues of homologous peptides presented by the MHC molecules to promote specific cellular responses. The preference for distinct TCR contacts depends on neither the affinity/avidity of TCR engagement (except in the most extreme ranges), nor the maturity of engaged T cells. Thus, different portions of the TCR ligand appear capable of biasing T cells toward specific biological responses. These findings explain differences in functional versatility of TCR ligands, as well as anomalies in the relationship between affinity/avidity of the TCR for the peptide/MHC and cellular responses of T cells.

Amino Acid Sequence↗
PubMed2004

HLA-A2-restricted CD8+-cytotoxic-T-cell responses to novel epitopes in Mycobacterium tuberculosis superoxide dismutase, alanine dehydrogenase, and glutamine synthetase.

Major histocompatibility complex class I-restricted CD8(+) cytotoxic T lymphocytes (CTL) are implicated in protective Th1 immunity to Mycobacterium tuberculosis infection. We report the identification of three novel HLA-A*0201-restricted CTL epitopes within mycobacterial superoxide dismutase (SodA), L-alanine dehydrogenase (AlaDH), and L-glutamine synthetase (GlnS) proteins.

Alanine Dehydrogenase↗
PubMed2003

Growth retardation as well as spleen and thymus involution in latent TGF-beta binding protein (Ltbp)-3 null mice.

The latent TGF-beta binding protein (LTBP)-3 is an extracellular matrix (ECM) protein that binds the small latent complex (SLC) of TGF-beta. Disruption of the Ltbp-3 gene by homologous recombination in mice yields mutant animals that display multiple skeletal abnormalities. In addition, these mice have retarded growth. On an inbred 129 SvEv background, half of the Ltbp-3 mutant mice die between 3 and 4 weeks after birth. These mice show severe involution of the thymus and spleen and a sharp reduction in the numbers of CD4/CD8 double positive T-cells in the thymus. The thymus and spleen defect is caused by elevated corticosterone levels in the serum and can be reversed by injection of aminoglutethimide (AMG), an inhibitor of steroid synthesis. This result indicates that the thymus and spleen defect is a secondary defect due to high corticosterone levels probably induced by stress of unknown etiology.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Could TCR antagonism explain associations between MHC genes and disease?

Alleles of major histocompatibility complex (MHC) loci are associated with certain types of diseases, including those of infectious and autoimmune origin. MHC products can promote susceptibility or resistance to disease by stimulating or inhibiting immune responses. Recent evidence suggests that MHC-associated peptides derived from self-proteins can act as antagonists of T-cell activation, thereby inhibiting immune responses to antigens. We suggest that self-peptide-promoted antagonism might explain some associations between MHC alleles and particular chronic diseases.

Disease Susceptibility↗
PubMed2002

The role of fibroblasts in thymocyte-positive selection.

Mice with fibroblast-specific expression of TAP-1 were generated by expressing the TAP-1 transgene under the control of the fibroblast-specific protein (FSP) 1 promoter/enhancer on TAP-1-deficient background. MHC class I expression in primary fibroblast cultures isolated from the resulting strain mimicked that of wild-type counterparts. MHC class I was detected in both types of fibroblasts following treatment with IFN-alphabeta. Positive selection of CD4(-)CD8(+) thymocytes was observed in neither adult nor fetal/neonatal thymus of transgenic mice. IFN-alphabeta-induced expression of MHC class I rescued positive selection of CD4(-)CD8(+) T cells in fetal thymic organ cultures, but not in adult mice. Contrary to previous suggestions, our results indicate a limited role of fibroblasts in promoting positive selection. In addition, the results suggest that positive selection may occur by a different mechanism in fetal vs adult thymus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Editing autoreactive TCR enables efficient positive selection.

Allelic exclusion is inefficient at the TCRalpha locus, allowing a sizeable portion of T cells to carry two functional TCRs. The potential danger of dual TCR expression is a rescue of autoreactive TCRs during selection in the thymus and subsequent development of autoimmunity. In this study, we examine the reason(s) for replacing an autoreactive TCR and for allowing the survival of cells carrying two TCRs. We compared development of TCR transgenic CD4(+)CD8(-) thymocytes in the presence or absence of MHC class II autoantigen that does not induce deletion of thymocytes. Contrary to the expected negative effect of the presence of autoantigen, approximately 100% more CD4(+)CD8(-) thymocytes were found in the presence of MHC class II autoantigen than in the neutral background. A further increase in the strength of autoantigenic signal via expression of a human CD4 transgene led to an additional increase in the numbers of CD4(+)CD8(-) thymocytes. Thus, editing autoreactive TCR results in more efficient positive selection, and this may be both a reason and a reward for risking autoimmunity.

Alleles↗
PubMed2002

Factors influencing the patterns of T lymphocyte allorecognition.

BACKGROUND: Strong alloreactive T cell responses are a menace in transplantation surgery and their menagement requires understanding the basis of alloreactivity. Alloantigen recognition can be peptide independent, peptide specific, or peptide dependent. The mechanisms influencing each recognition pattern are largely unknown. METHODS: Peptide dependence was examined in vitro by adding peptides to antigen processing-deficient cell line used as target in cytotoxic T cell assays. Responses to major histocompatibility complex (MHC) alleles most homologous to self were recently shown to be more peptide dependent than to those with lesser homology to self. Hence, peptide reactivity in vivo was estimated based on relative strengths of alloreactive responses to more homologous and less homologous MHC alleles. RESULTS: Alloreactive CD8+ TCR repertoire in beta2-microglobulin-deficient mice is preferentially peptide independent. The peptide-specific component is acquired as a function of wild-type thymic epithelium grafting. Irrespective of the presence of the peptide-specific component, in vivo alloantigenic priming was associated with a greater sensitivity to the MHC structure than was in vitro priming. CONCLUSIONS: Thymic positive selection and the mode of alloreactivity induction are the major independent factors determining the patterns of alloantigen recognition.

Animals↗
PubMed2002

Rare, structurally homologous self-peptides promote thymocyte positive selection.

Although it is clear that positive selection of T cells involves recognition of specific self-peptide/MHC complexes, the nature of these self-ligands and their relationship to the cognate antigen are controversial. Here we used two complementary strategies to identify naturally occurring self-peptides able to induce positive selection of T cells bearing a specific T cell receptor, OT-I. Both the bioassay- and bioinformatics-based strategies identified the same self-peptides, derived from F-actin capping protein and beta-catenin. These peptides displayed charge conservation at two key TCR contact residues. The biological activity of 43 other self-peptides and of complex peptide libraries directly correlated to the extent of conservation at TCR contact residues. These results demonstrate that selecting self-peptides are rare and can be identified by homology-based search strategies.

Actin Depolymerizing Factors↗
PubMed2002

Genomics-based identification of self-ligands with T cell receptor-specific biological activity.

Self-peptide/major histocompatibility complex (MHC) complexes profoundly influence the biology of T lymphocytes. They promote the selection of the T cell receptor (TCR) repertoire in the thymus, maintain the homeostasis of peripheral T cells prior to encounter with antigen, and modify the responsiveness of T cells to foreign antigens. In addition, they can serve as antigens for autoaggressive T cells that induce autoimmune diseases. The complete sequencing of the genomes of human, mouse, and many pathogenic organisms now provides us with a comprehensive list of all possible proteins that may be the source of foreign antigenic and self-peptides. A computational approach using profile-based similarity searches on potential self-MHC-binding peptides can be used to efficiently predict self-peptides with biological activities. The common feature of the identified peptides is similarity to antigen. Thus, self-peptides may form 'hazy' images of the universe of antigens that are used as templates to create and maintain the TCR repertoire.

Amino Acid Motifs↗