Biomedical subjects

Raquel Tarazona

Publications and source records attributed to Raquel Tarazona.

12 recordsLinked to original sources

PubMed2006

Lymphocyte activation in response to melanoma: interaction of NK-associated receptors and their ligands.

In recent years, studies on the molecular and cellular mechanisms of immune responses against melanoma have contributed to a better understanding of how these tumours can be recognised by cytotoxic cells and the mechanisms they have developed to escape from innate and adaptive immunity. Lysis of melanoma cells by natural killer (NK) cells and cytolytic T cells is the result of a fine balance between signals transmitted by activating and inhibitory receptors. In addition to the T cell receptor, these were initially described as NK cell-associated receptors (NKRs) and were later also found on subsets of T lymphocytes, particularly effector-memory and terminally differentiated CD8 T cells. An increase of NKR(+)CD8(+) T cells has been found in melanoma patients, correlating with the expansion of differentiated effector CD8(+)CD28(null) CD27(null) T cells. NKRs can regulate the lysis of target cells expressing appropriate ligands. Activating receptors recognise ligands on tumours whereas inhibitory receptors are specific for MHC class I antigens and sense missing self. Altered expression of MHC class I antigens is frequently found on melanoma cells, preventing recognition by specific cytolytic T cells but favouring NK cell recognition. Changes in the expression of NKR-ligands in melanoma contribute in explaining the differences in the capacity of cytotoxic immune cells to control melanoma growth and dissemination.

Humans↗

PubMed2006

Aging and innate immunity.

Adaptive immunity undergoes severe deterioration with age and represents the main problem in the elderly. However, evidence accumulated over the last decade supports the hypothesis that aging also has a profound impact on innate immunity, which in turn markedly impacts the health and longevity of older people.

Aging↗

PubMed2005

CD8 T cells expressing NK associated receptors are increased in melanoma patients and display an effector phenotype.

CD8+ T cells can express NK-associated receptors (NKRs) that may regulate their cytolytic function. We have characterized the expression of several NKRs on peripheral blood CD8+ T cells from melanoma patients and compared them to age-matched healthy donors. The analysis performed includes HLA class I specific receptors (KIRs, LILRB1 and CD94/NKG2) and other NK receptors like CD57, CD56 and CD16. Melanoma patients showed a higher variability in the expression of NKRs on circulating CD8+ T cells than age-matched healthy donors. NKR expression on CD8+ T cells from melanoma patients showed a significant increase of KIR2DL2/L3/S2 (mAb gl183), CD244, CD57, CD56 and CD16. We have also found an increase of CD8+ CD28- CD27- T cells in melanoma patients. This subset represents terminally differentiated effector cells expressing CD244 and high levels of perforin. The expression of NKRs was also mainly restricted to this T cell subset. Altogether, circulating CD8+ T cells from melanoma patients display a distinct phenotype characterized by downregulation of costimulatory molecules and higher expression of NKRs. We suggest that the increased expression of NKRs on T cells may contribute to the final outcome of the immune response against melanoma both stimulating or inhibiting activation and differentiation to effector cells. Blocking inhibitory receptor function and enhancing activating receptors may represent new strategies with therapeutic potential against melanoma.

Adult↗

PubMed2004

The B-ring substituent at C-7 of colchicine and the alpha-C-terminus of tubulin communicate through the "tail-body" interaction.

The carboxy terminals of alphabeta-tubulins are flexible regions rich in acidic amino acid residues that play an inhibitory role in the polymerization of tubulin to microtubules. We have shown that the binding of colchicine and its B-ring analogs (with C-7 substituents) to tubulin are pH sensitive and have high activation energies. Under identical conditions, the binding of analogs without C-7 substituents is pH independent and has lower activation energy. Beta-C-terminus-truncated tubulin (alphabeta(s)) shows similar pH sensitivity and activation energy to native tubulin (alphabeta). Removal of the C-termini of both subunits of tubulin (alpha(s)beta(s)) or the binding of a basic peptide P2 to the negatively charged alpha-C-terminus of tubulin causes a colchicine-tubulin interaction independent of pH with a low activation energy. Tubulin dimer structure shows that the C-terminal alpha-tail is too far from the colchicine binding site to interact directly with the bound colchicine. Therefore, it is likely that the interaction of the alpha-C-terminus with the main body of tubulin indirectly affects the colchicine-tubulin interaction via conformational changes in the main body. We therefore conclude that in the presence of tail-body interaction, a B-ring substituent makes contact with the alpha-tubulin and induces significant conformational changes in alpha-tubulin.

Animals↗

PubMed2004

Expression of NK-associated receptors on cytotoxic T cells from melanoma patients: a two-edged sword?

The coexistence of tumor progression with a tumor-specific immune response constitutes a major paradox of tumor immunity. During the last decade, the presence of cytotoxic T lymphocytes (CTLs) recognising melanoma-associated antigens has been unequivocally demonstrated in numerous different in vivo and in vitro models. However, most often these melanoma-specific T lymphocytes do not control tumor growth. Several mechanisms that involve changes in melanoma phenotype and/or in T-cell differentiation and function could explain the inability of the immune response to control melanoma. In the last few years it has been demonstrated that cellular cytotoxicity is the result of a balance between activating signals triggered by the TCR and costimulatory molecules and inhibitory signals triggered by inhibitory receptors expressed by the CTL. Because the final outcome of the immune response against melanoma depends on the balance between activating and inhibitory signals, the expression de novo on melanoma cells of ligands for inhibitory NKRs and the down-regulation of costimulatory molecules may favor the escape of tumor cells from immunosurveillance. In this paper we review how altered expression of molecules required for T-cell costimulation could result in impaired lysis of melanoma. The modulation of antimelanoma T-cell responses by a group of receptors originally described on NK cells (NK-associated receptors) but which are now known also to be expressed on a subset of cytolytic effector cells is reviewed. We hypothesize that the expression of ligands for NKRs on melanoma cells may contribute to T-cell-mediated immune responses against melanoma either enhancing or inhibiting activation and differentiation to effector cells. Blocking inhibitory receptors or increasing activating receptors could result in new strategies to improve T-cell-mediated rejection of melanoma.

Antigens, CD↗

PubMed2002

NK-associated receptors on CD8 T cells from treatment-naive HIV-infected individuals: defective expression of CD56.

OBJECTIVES: This study addresses the detailed expression of natural killer (NK)- associated receptors on CD8 T lymphocytes in treatment-naive HIV-infected individuals. DESIGN: Experimental study analysing the expression of NK-associated receptors on peripheral blood T lymphocytes from HIV-infected individuals compared with healthy controls. METHODS: Flow cytometry was used to analyse the expression of CD56, CD16, CD94, NKG2A, NKB1, CD161, CD244, and perforin, according to the CD28 phenotype, on CD8(bright) T cells obtained from treatment-naive HIV-infected individuals and from healthy controls. RESULTS: The results showed that CD8(bright) T cells from treatment-naive HIV-infected individuals had a decreased expression of CD56 and that CD8(bright)CD56 cell numbers correlated with CD4 cell counts. NK-associated markers were preferentially expressed on CD8(bright)CD28 negative T cells, both in healthy controls and HIV-infected individuals. An increased expression of CD94, CD244, and perforin, which was the consequence of the expansion of the CD8(bright)CD28 negative T-cell subset, was also observed in HIV infection. CONCLUSIONS: As the CD8(bright)CD56 T cells are the mature cytolytic effector cells, the defective expression of CD56 on CD8(bright) T cells shown in HIV-infected individuals could be involved in the decreased peripheral blood T-cell cytotoxicity found in HIV infection.

Adult↗

PubMed2002

Inhibition of CD28-mediated natural cytotoxicity by KIR2DL2 does not require p56(lck) in the NK cell line YT-Indy.

CD28 functions as a cytotoxicity activation receptor in the NK cell line YT-Indy. To analyze the requirement of p56(lck) kinase in the function of killer inhibitory receptors, we transfected the p56(lck) negative YT-Indy cell line with the cl43 gene encoding for KIR2DL2. Pervanadate treatment revealed KIR2DL2 phosphorylation in YT-Indy-cl43, as well as SHP1/SHP2 recruitment. YT-Indy-cl43 cells were inhibited in their ability to lyse target cells expressing HLA-Cw3, a ligand for KIR2DL2. This inhibition was blocked by anti-KIR2DL2 or anti-HLA class I mAb. CD28 crosslinking on YT-Indy-cl43 enhanced tyrosine phosphorylation of PLC-gamma1. The simultaneous ligation of KIR2DL2 with mAb resulted in a decrease in CD28-induced tyrosine phosphorylation of PLC-gamma1 confirming that dephosphorylation of this protein is involved in the KIR2DL2-induced inhibition of CD28-mediated cytotoxicity. As YT-Indy-cl43 did not express detectable levels of p56(lck), these results indicate that this kinase is not required for transmitting the negative signals generated by KIR2DL2 ligation.

CD28 Antigens↗

PubMed2002

Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals.

Human immunodeficiency virus-I (HIV-1) infected patients show a gradual loss of natural killer (NK) cells that correlates with disease progression. However, the effect of HIV-1 infection on different NK cell subsets has not been fully characterized. In healthy individuals most NK cells are CD3-CD56+ and two different subpopulations, CD56(dim) and CD56(bright), can be distinguished by the mean fluorescence intensity. Although it was originally suggested that CD56(bright) NK cells represent the precursors of the CD56dim subpopulation, recent cumulative data indicate that CD56(bright) and CD56(dim) NK cells are phenotypically, functionally, and developmentally different NK cell subsets. In this study, the analysis of CD56(bright) and CD56(dim) NK subsets showed that neither the number nor the phenotype of CD56(bright) NK cells were significantly altered in treatment-naive HIV-1-infected individuals, whereas the number of CD56(dim) NK cells was decreased. We also have studied NK cell subsets defined by the expression of CD56 in combination with CD16, CD161, or CD94 molecules. Our results demonstrated a preferential decrease of CD3-CD56+ NK cells coexpressing CD16 and CD161 but lacking CD94 molecules. On the contrary an increased percentage of NK cells that do not express CD56 molecules but express CD16, CD161, or CD94 was also found in HIV-1-infected individuals. As it has been proposed that these CD56-negative NK cells expressing other NK cell receptors represent immature NK cells with low cytolytic capacity, our results support that a defective differentiation from immature CD56 negative NK cells to mature CD56(dim) NK cells occurs in HIV-1 infection.

Adult↗

PubMedDate not supplied

Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity.

Scientific and clinical advances in the last century have led to increased numbers of individuals living to older ages. Thus a major concern is how to live these years with a high quality of life. The ageing immune system is less well able to cope with infectious diseases than the youthful immune system probably as a consequence of altered immune response to pathogens. Thus, both innate and adaptive immune responses show age-related changes that could be decisive for healthy ageing and survival. Longitudinal studies in healthy elderly have allowed the definition of the ''immune risk phenotype" (IRP) a predictor of mortality in elderly individuals that is based on several parameters of the adaptive immune response. Here, we hypothesize that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP. It will be important to include assays of NK cell markers and functions in future longitudinal studies in order to investigate this point in detail as well as to consider the trace element zinc as an essential co-factor for optimal NK cell activity.

Aged, 80 and over↗

PubMedDate not supplied

Decreased frequency and proliferative response of invariant Valpha24Vbeta11 natural killer T (iNKT) cells in healthy elderly.

Invariant natural killer T (iNKT) cells represent a well-established T cell lineage characterised in humans by TCR consisting of an invariant alpha chain encoded by Valpha24-JalphaQ genes, paired preferentially with a Vbeta11 chain. iNKT cells also share some characteristics with NK cells, such as the expression of the NK-associated receptor CD161 in humans. The T cell immune response is the most dramatically affected by ageing, although age-associated alterations in the phenotype and function of other cells of the immune system have been demonstrated. Despite the importance of iNKT cells in the regulation of the immune response, there are a limited number of studies on the effect of ageing on peripheral blood iNKT cells. Thus, in this work we analyse the effect of ageing on peripheral blood Valpha24(+)Vbeta11(+) iNKT cells by studying their frequency, phenotype and proliferative function in elderly individuals fulfilling the SENIEUR criteria of healthy ageing compared with healthy young donors. Our results demonstrated a significant decrease of the percentage of Valpha24(+)Vbeta11(+) iNKT cells in elderly donors. No significant differences were found in the expression of CD27, CD28, CD45RO, CD45RA(bright), CD161, CD94 and NKG2D on iNKT cells from young and elderly individuals. Proliferation of Valpha24(+)Vbeta11(+) iNKT cells in response to alpha-GalCer and IL2 was analysed by calculating the cumulative population doubling (PD) after 14 days of culture. The PD levels were lower in the elderly indicating that Valpha24(+)Vbeta11(+) iNKT cells from healthy elderly subjects had an impaired proliferative capacity. These results indicate that ageing associates with a significant decline in the percentage and proliferative response of peripheral blood iNKT cells. Given the important immunoregulatory role of iNKT cells, these alterations in their number and function could contribute to the deleterious immune response in the elderly.

Adult↗

PubMedDate not supplied

Basic biology and clinical impact of immunosenescence.

Immunosenescence is an age-associated decline of immunity involving multiorgan changes. As the mean age of the population increases, an increase of diverse pathologies associated with immunosenescence has been observed in the developed countries. Age-related changes in the immune system contribute to the increased incidence and severity of infectious diseases and possibly cancer in the elderly. Moreover, in young individuals chronic activation of the immune system (as occurs in autoimmune diseases, cancer, HIV infection and other chronic infections) induces changes in the immune response that parallel those observed in elderly individuals. An interdisciplinary approach to immunosenescence including investigation of the molecular and cellular mechanisms and clinical aspects is being utilised by the EU program "Immunology and Ageing in Europe" (ImAginE, QLK6-CT-1999-02031), the second major international conference of which took place in Córdoba, Spain, 22-26th March, 2001). We briefly summarise some of the highlights of the meeting here, and bring together in this special issue a collection of peer-reviewed papers reflecting the broad approach to immunosenescence currently being applied.

Aging↗

PubMedDate not supplied

Valpha24+ NKT cells are decreased in elderly humans.

Natural killer T (NKT) cells represent a novel cell lineage characterized by the restricted expression of an invariant TCRalpha chain encoded by Valpha24/JalphaQ gene segments in humans and Valpha14/Jalpha281+ in mice. Different aspects of the immune response are severely affected by age. Thus, we have studied the effect of aging on NKT cells from healthy elderly individuals. Our results demonstrated a decreased percentage of CD3+Valpha24+ cells in peripheral blood from elderly donors, whereas mainstream T lymphocytes showed an age-associated decrease in the expression of CD28, the vast majority of CD3+Valpha24+ cells from old individuals were CD28+. A significant increase in the percentage of Valpha24+ cells with the CD4-CD8+ phenotype was also found in the elderly, indicating a redistribution of Valpha24+ subsets according to the CD4/CD8 phenotype. Given the important immunoregulatory role of these cells, the decrease of NKT cells will contribute to the deleterious immune response in the elderly.

Adult↗