Subject(s)
DNA Copy Number Variations/genetics , Genetic Markers/genetics , Genetic Predisposition to Disease , Germ-Line Mutation/genetics , Inheritance Patterns/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Lymphoproliferative Disorders/genetics , Female , Genome, Human , Humans , Male , Oligonucleotide Array Sequence Analysis , Pedigree , Polymorphism, Single Nucleotide/genetics , PrognosisABSTRACT
Hematopoietic stem cell transplantation (HSCT) is complicated by unwelcome side-effects that arise on the basis of an altered immune system. Infectious complications and alloreactive T-cell responses trigger a process of ongoing immune activation and inflammation. Negative-feedback mechanisms to counteract inflammation involve the induction of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO), which mediates anti-inflammatory activities and T-cell inhibition via tryptophan catabolism. However, persistent immune activation and generalized release of pro-inflammatory cytokines deviate immune regulation towards chronic suppression incapable to abrogate the inflammatory response. This review focuses on the unique role of tryptophan catabolism in modulating inflammatory processes and T-cell responses after HSCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology , Animals , Humans , T-Lymphocytes/immunologyABSTRACT
So far, very few studies exist on the naïve T cell population of elderly persons. Only recently an increase in the percentage of long lived CD4(+)CD31(-) naïve T cells has been claimed to occur with aging. We, therefore, characterised CD31(+) and CD31(-) CD45RA(+) CD4(+) T cells in young and healthy elderly persons. The production of IL-2 and IFN-gamma by the different subpopulations was studied following stimulation with PMA and Ionomycin. The expression of CD28, CD11a, CD62L, CXCR3 and CCR7 was also analysed. The results of this study demonstrate a pronounced increase in the percentage of CD31(-) CD45RA(+) T cells within the CD4 subpopulation of elderly persons. Both, CD31(-) and CD31(+) CD45RA(+) cells expressed CD28, CD62L, were CD11a (dim) and produced IL-2 but no IFN-gamma. This phenotype confirms that they were naïve T cells. IL-2 production by naïve T cells was not impaired in elderly persons. Interestingly, CD31(+) as well as CD31(-) naïve T cells contained a subpopulation of CXCR3(+) cells in elderly individuals, but not in young ones. In spite of expressing this chemokine receptor that enables the cells to migrate into inflammatory tissues, they were still CCR7(+) and CD62L(+). We speculate that due to previous contact with local environmental factors, this subset of naïve T cells acquires a different chemokine receptor phenotype, resulting in an altered migratory capacity in old age. Aberrant contact with antigen and effector cell differentiation in unorthodox locations may be the consequence. This could also affect Th1/Th2 polarisation, which is known to be impaired in elderly persons.
Subject(s)
Aging/immunology , CD4-Positive T-Lymphocytes/metabolism , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Receptors, Chemokine/metabolism , Adult , Aged , Biomarkers , CD4 Antigens/metabolism , CD4-Positive T-Lymphocytes/cytology , Cell Adhesion/immunology , Cell Movement/immunology , Cohort Studies , Female , Humans , Immunophenotyping , Leukocyte Common Antigens/metabolism , Male , Middle Aged , Receptors, CXCR3 , Th1 Cells/cytology , Th1 Cells/metabolism , Th2 Cells/cytology , Th2 Cells/metabolismABSTRACT
The stimulatory properties of soluble recombinant influenza nucleoprotein (NP) on purified CD4(+) and CD8(+) T cells from young and elderly individuals were studied. Recombinant influenza NP failed to induce proliferation of resting CD4(+) and CD8(+) T cells in the absence of IL-2. Addition of small amounts of IL-2, however, led to strong proliferation of resting CD4(+) and CD8(+) T cells from young and elderly donors. NP-reactive CD4(+) and CD8(+) T cell lines from both age groups grew equally well under long-term culture conditions. T cell lines raised to live influenza virus could recognize recombinant influenza NP and showed a substantial proliferative response. Stimulation of CD8(+) T cells is presumably due to cross-presentation, as EBV-transformed MHC class I-positive cell lines, which are incapable of antigen processing, stimulated live influenza virus-reactive CD8(+) T cell lines when loaded with NP-derived immunodominant peptides but not following loading with the whole NP molecule. Vaccines containing recombinant influenza NP might confer cross-protective immunity and could therefore be especially useful in cases of major epidemics or pandemics.