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Repertoire Diversity (repertoire + diversity)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Microbial colonization induces oligoclonal expansions of intraepithelial CD8 T cells in the gut

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004
Lars Helgeland
Abstract Two populations of CD8+ IEL generally express restricted, but apparently random and non-overlapping TCR repertoires. Previous studies in mice suggested that this could be explained by a dual origin of CD8+ IEL, i.e. that CD8,,+ IEL derive from a few peripheral CD8+ T cell lymphoblasts stimulated by microbial antigens in gut-associated lymphoid tissue, whereas CD8,,+ IEL descend from an inefficient intestinal maturation pathway. We show here that the gut mucosa, instead, becomes seeded with surprisingly broad and generally non-overlapping CD8 IEL repertoires and that oligoclonality is induced locally after microbial colonization. In germ-free (GF) rats, both CD8,,+ and CD8,,+ IEL displayed surprisingly diverse TCR V, repertoires, although ,-chain diversity tended to be somewhat restricted in the CD8,,+ subset. CDR3 length displays in individual V,-C, and V,-J, combinations generally revealed polyclonal distributions over 6,11 different lengths, similar to CD8+ lymph node T cells, and CDR3, sequencing provided further documentation of repertoire diversity. By contrast, in ex-GF rats colonized with normal commensal microflora, both CD8,,+ and CD8,,+ IEL displayed oligoclonal CDR3 length distributions for most of the V, genes analyzed. Our data suggest that microbial colonization induces apparently random clonal expansions of CD8,,+ and CD8,,+ IEL locally in the gut. [source]

Thiazolidinedione treatment and constitutive-PPAR, activation induces ectopic adipogenesis and promotes age-related thymic involution

AGING CELL, Issue 4 2010
Yun-Hee Youm
Summary Age-related thymic involution is characterized by reduction in T cell production together with ectopic adipocyte development within the hematopoietic and thymic niches. Peroxisome proliferator-activated receptor gamma (PPAR,) is required for adipocyte development, glucose homeostasis and is a target for several insulin-sensitizing drugs. Our prior studies showed that age-related elevation of PPAR, expression in thymic stromal cells is associated with thymic involution. Here, using clinically relevant pharmacological and genetic manipulations in mouse models, we provide evidence that activation of PPAR, leads to reduction in thymopoiesis. Treatment of aged mice with antihyperglycemic PPAR,-ligand class of thiazolidinedione drug, rosiglitazone caused robust thymic expression of classical pro-adipogenic transcripts. Rosiglitazone reduced thymic cellularity, lowered the naïve T cell number and T cell receptor excision circles (TRECs) indicative of compromised thymopoiesis. To directly investigate whether PPAR, activation induces thymic involution, we created transgenic mice with constitutive-active PPAR, (CA-PPARg) fusion protein in cells of adipogenic lineage. Importantly, CA-PPAR, transgene was expressed in thymus and in fibroblast-specific protein-1/S100A4 (FSP1+) cells, a marker of secondary mesenchymal cells. The CAPPAR, fusion protein mimicked the liganded PPAR, receptor and the transgenic mice displayed increased ectopic thymic adipogenesis and reduced thymopoiesis. Furthermore, the reduction in thymopoiesis in CA-PPAR, mice was associated with higher bone marrow adiposity and lower hematopoietic stem cell progenitor pool. Consistent with lower thymic output, CAPPAR, transgenic mice had restricted T cell receptor repertoire diversity. Collectively, our data suggest that activation of PPAR, accelerates thymic aging and thymus-specific PPAR, antagonist may forestall age-related decline in T cell diversity. [source]

B-cell diversity decreases in old age and is correlated with poor health status

AGING CELL, Issue 1 2009
Kate L. Gibson
Summary Older people suffer from a decline in immune system, which affects their ability to respond to infections and to raise efficient responses to vaccines. Effective and specific antibodies in responses from older individuals are decreased in favour of non-specific antibody production. We investigated the B-cell repertoire in DNA samples from peripheral blood of individuals aged 86,94 years, and a control group aged 19,54 years, using spectratype analysis of the IGHV complementarity determining region (CDR)3. We found that a proportion of older individuals had a dramatic collapse in their B-cell repertoire diversity. Sequencing of polymerase chain reaction products from a selection of samples indicated that this loss of diversity was characterized by clonal expansions of B cells in vivo. Statistical analysis of the spectratypes enabled objective comparisons and showed that loss of diversity correlated very strongly with the general health status of the individuals; a distorted spectratype can be used to predict frailty. Correlations with survival and vitamin B12 status were also seen. We conclude that B-cell diversity can decrease dramatically with age and may have important implications for the immune health of older people. B-cell immune frailty is also a marker of general frailty. [source]

T- and B-cell immune reconstitution and clinical outcome in patients with multiple myeloma receiving T-cell-depleted, reduced-intensity allogeneic stem cell transplantation with an alemtuzumab-containing conditioning regimen followed by escalated donor lymphocyte infusions

BRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2003
Shirley D'Sa
Summary. Immune reconstitution after conventional allogeneic transplantation is a major determinant of survival. We conducted a detailed investigation of T- and B-cell immune reconstitution and clinical outcome in 19 patients with multiple myeloma undergoing reduced-intensity stem cell transplantation using in vivo T-cell depletion with alemtuzumab. These patients experienced delayed T-cell recovery, particularly in the naïve (CD45 RA+) CD4 compartment. T-cell receptor spectratype analysis showed a reduced repertoire diversity, which improved rapidly after the administration of donor leucocyte infusions and subsequent conversion to full donor T-cell chimaerism. Post-transplant recovery of CD19+ B cells was also delayed for up to 18 months. Spectratype analysis of IgH CDR3 repertoire revealed a gradual normalization in IgM spectratype complexity by 6,12 months after transplant. There was a high incidence of viral infection, particularly cytomegalovirus reactivation, but the regimen-related mortality was low, perhaps because of the very low incidence of acute graft-versus-host disease (GVHD; grade I-II skin GVHD was seen in 5/19 patients). Over 80% of all patients have relapsed at a median of 283 (range 153,895) d after transplant, suggesting that the initially low rate of GVHD comes at a high price with regard to the desired graft-versus-myeloma effect. [source]