Browsing by Author "Sousa, A. E."
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- Attenuated vaccines for AIDS?Publication . Victorino, R. M.; Sousa, A. E.
- Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recoveryPublication . Sousa, A. E.; Chaves, A. F.; Doroana, M.; Antunes, F.; Victorino, R. M. M.Fas, CD40L and OX40 are members of the tumour necrosis factor (TNF) receptor superfamily with critical roles in T cell activation and death, B cell function, dendritic cell maturation and leucocyte traffic regulation. The aim of this study was to evaluate the effects of anti-retroviral therapy (HAART) on CD40L, OX40 and Fas expression on freshly isolated peripheral blood T cells by three-colour flow cytometry and compare them with lymphoproliferative responses, peripheral blood cell counts and viral load. Fourteen asymptomatic HIV-1+ patients treated with Lamivudine, Stavudine and Nelfinavir were prospectively investigated sequentially for 48 weeks. At baseline, patients exhibited significantly enhanced proportions and counts of CD40L+ and OX40+ cells within the CD4 subset which were corrected by weeks 8-16 of HAART. Interestingly, in the five patients showing viral load rebound during therapy in spite of increasing CD4 counts, the reduction of the levels of these costimulatory molecules was similarly maintained. Therapy induced a decrease in the over-expression of Fas, particularly in the CD4 subset where normal levels were reached at week 8. This reduction occurred in parallel with the major recovery of lymphoproliferative responses. Higher basal levels and lower reduction of Fas were associated with suboptimal suppression of viraemia. In conclusion, this previously undescribed increased expression of CD40L and OX40 may play a role in the HIV-associated pan-immune activation and represent a possible target for immunointervention, as suggested for several immunologically mediated diseases. Moreover, HAART induced an early correction of the over-expression of Fas, CD40L and OX40 in CD4 T cells which could be involved in the recovery of the cell traffic disturbances and in the T cell renewal capacity.
- Efficient thymopoiesis contributes to the maintenance of peripheral CD4 T cells during chronic human immunodeficiency virus type 2 infectionPublication . Gautier, D.; Beq, S.; Cortesão, C. S.; Sousa, A. E.; Cheynier, R.Human immunodeficiency virus type 2 (HIV-2) infection leads to a lifelong asymptomatic period in the majority of patients. Even in patients with progressive disease, a slow CD4 count decline characterizes the chronic phase of HIV-2 infection, suggesting that peripheral T-cell homeostasis is controlled better following HIV-2 infection than following HIV-1 infection. Herein we showed that, in contrast to HIV-1-infected patients, HIV-2-infected patients demonstrate enhanced thymic function compared to age-matched healthy individuals. The correlation between higher thymic production and lower CD4 T-cell loss in these patients suggests that efficient thymopoiesis is implicated in the long-lasting maintenance of CD4 T-cell counts in HIV-2 disease.
- Expansion of circulating Foxp3+D25bright CD4+ T cells during specific venom immunotherapyPublication . Pereira-Santos, M. C.; Baptista, A. P.; Melo, A.; Alves, R. R.; Soares, R. S.; Pedro, E.; Pereira-Barbosa, M.; Victorino, R. M. M.; Sousa, A. E.BACKGROUND: Venom immunotherapy (VIT) induces long-lasting immune tolerance to hymenoptera venom antigens, but the underlying mechanisms are not yet clarified. Regulatory T cells are thought to play an important role in allergic diseases and tolerance induction during specific immunotherapy. AIM: Characterize longitudinally the impact of VIT on the pool of circulating regulatory T cells. METHODS: Fourteen hymenoptera venom-allergic patients with severe reactions (grades III-IV) were studied before, 6 and 12 months after starting ultra-rush VIT. Freshly isolated peripheral blood mononuclear cells were surface stained with a panel of markers of T cell differentiation and intracellularly for CTLA-4 and Foxp3 and analysed by flow cytometry. foxp3 mRNA was quantified by real-time PCR. VIT responses were assessed by measuring specific IgG4 and IgE levels. Eleven individuals with no history of insect venom allergy were studied as controls. RESULTS: VIT induces a significant progressive increase in both the proportion and the absolute numbers of regulatory T cells defined as CD25bright and/or Foxp3+ CD4+ T cells. These changes are not related to alterations in the expression of activation markers or imbalances in the naïve/memory T cell compartments. foxp3 mRNA levels also increased significantly during VIT. Of note, the increase in circulating regulatory T cell counts significantly correlates with the venom-specific IgG4/IgE ratio shift. CONCLUSION: VIT is associated with a progressive expansion of circulating regulatory T cells, supporting a role for these cells in tolerance induction.
- First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID) : a report of 2 casesPublication . Markert, M. L.; Marques, J. G.; Neven, B.; Devlin, B. H.; McCarthy, E. A.; Chinn, I. K.; Albuquerque, A. S.; Silva, S. L.; Pignata, C.; de Saint Basile, G.; Victorino, R. M.; Picard, C.; Debre, M.; Mahlaoui, N.; Fischer, A.; Sousa, A. E.FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm(3) and 1232/mm(3) CD3(+) cells, 647/mm(3) and 868/mm(3) CD4(+) T cells, 213/mm(3) and 425/mm(3) naive CD4(+) T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3(+) cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discontinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.
- Gag-specific CD4+ T-cell frequency is inversely correlated with proviral load and directly correlated with immune activation in infection with human immunodeficiency virus type 2 (HIV-2) but not HIV-1Publication . Foxall, R. B.; Cortesão, C. S.; Albuquerque, A. S.; Soares, R. S.; Victorino, R. M.; Sousa, A. E.Human immunodeficiency virus type 2 (HIV-2) infection, unlike HIV-1 infection, is normally characterized by low rates of CD4 depletion and low-to-undetectable viremia. We found that the frequency of Gag-specific CD4(+) T cells featured positive correlations with the expression of markers of CD4 activation and a negative correlation with peripheral blood mononuclear cell-associated proviral load in infection with HIV-2, in contrast with HIV-1. Moreover, HIV-2-infected individuals exhibited a greater ability to respond to HIV-1 Gag peptides (heterologous responses). Our data suggest a potential link between HIV-2-specific CD4 responses, immune activation, and viral control, which may in turn relate to the better prognosis associated with HIV-2 infection.
- Gut disruption in HIV-2 infection despite reduced viremiaPublication . Fernandes, S. M.; Pires, A. R.; Ferreira, C.; Tendeiro, R.; Correia, L.; Paulo, S. E.; Victorino, R. M.; Sousa, A. E.HIV-2 infection is highly prevalent inWest Africa and has been increasingly observed in non-African countries, mostly associated with migratory populations [1]. It has a much more benign course and lower viremia than HIV-1 [2], though with similar clinical spectra. Half of the HIV-2 infected patients with less than 200 CD4+ T-cells/ml exhibit undetectable viremia, despite harbouring numbers of infected cells comparable to their HIV-1 counterparts [3]. Moreover, CD4+ T-cell loss occurs in direct association with progressive immune activation in both infections, though the depletion rate is much slower in HIV-2 [2,4]. HIV-1 disease progression has been linked to disruption of gut-associated lymphoid tissue (GALT)and increased levels of microbial translocation, leading to systemic immune activation. There are currently no data on the impact of HIV-2 on GALT. Here, we provide evidence of HIV-2 replication in the gut despite the low viremia, which was associated with major mucosal disruption and CD4+ T-cell depletion that recovered upon antiretroviral treatment (ART).
- Human FOXN1-deficiency is associated with αβ double-negative and FoxP3+ T-cell expansions that are distinctly modulated upon thymic transplantationPublication . Albuquerque, A. S.; Marques, J. G.; Silva, S. L.; Ligeiro, D.; Devlin, B. H.; Dutrieux, J.; Cheynier, R.; Pignata, C.; Victorino, R. M.; Markert, M. L.; Sousa, A. E.Forkhead box N1 (FOXN1) is a transcription factor crucial for thymic epithelium development and prevention of its involution. Investigation of a patient with a rare homozygous FOXN1 mutation (R255X), leading to alopecia universalis and thymus aplasia, unexpectedly revealed non-maternal circulating T-cells, and, strikingly, large numbers of aberrant doublenegative ab T-cells (CD4negCD8neg, DN) and regulatory-like T-cells. These data raise the possibility that a thymic rudiment persisted, allowing T-cell development, albeit with disturbances in positive/negative selection, as suggested by DN and FoxP3+ cell expansions. Although regulatory-like T-cell numbers normalized following HLA-mismatched thymic transplantation, the abDN subset persisted 5 years post-transplantation. Involution of thymus allograft likely occurred 3 years post-transplantation based on sj/bTREC ratio, which estimates intrathymic precursor T-cell divisions and, consequently, thymic explant output. Nevertheless, functional immune-competence was sustained, providing new insights for the design of immunological reconstitution strategies based on thymic transplantation, with potential applications in other clinical settings.
- Human regulatory T-cell development is dictated by Interleukin-2 and -15 expressed in a non-overlapping pattern in the thymusPublication . Caramalho, I.; Nunes-Silva, V.; Pires, A. R.; Mota, C.; Pinto, A. I.; Nunes-Cabaço, H.; Foxall, R. B.; Sousa, A. E.Thymus-derived FOXP3-expressing regulatory T-cells (tTregs) are master orchestrators of physiological and pathological immune responses, thus constituting ideal targets for the treatment of autoimmunity. Despite their clinical importance, the developmental program governing their differentiation in the human thymus remains poorly understood. Here, we investigated the role of common gamma-chain cytokines in human tTreg differentiation, by performing gain- and loss-of-function experiments in 3D and 2D postnatal thymic cultures. We identified IL-2 and IL-15 as key molecular determinants in this process and excluded a major function for IL-4, IL-7 and IL-21. Mechanistically, IL-2 and IL-15 were equally able to drive tTreg precursor differentiation into FOXP3(+) cells, and promote tTreg proliferation and survival. Both cytokines also increased the expression levels of molecules associated with effector function within FOXP3(+) subsets, supporting their involvement in tTreg functional maturation. Furthermore, we revealed that IL-2 and IL-15 are expressed in a non-overlapping pattern in the human thymus, with the former produced mainly by mature αβ and γδ thymocytes and the latter by monocyte/macrophages and B lymphocytes. Our results identify core mechanisms dictating human tTreg development, with IL-2 and IL-15 defining specific niches required for tTreg lineage stabilization and differentiation, with implications for their therapeutic targeting in autoimmune conditions.
- IL-7 sustains CD31 expression in human naive CD4+ T cells and preferentially expands the CD31+ subset in a PI3K-dependent mannerPublication . Azevedo, R. I.; Soares, M. V.; Barata, J. T.; Tendeiro, R.; Serra-Caetano, A.; Victorino, R. M.; Sousa, A. E.The CD31(+) subset of human naive CD4(+) T cells is thought to contain the population of cells that have recently emigrated from the thymus, while their CD31(-) counterparts have been proposed to originate from CD31(+) cells after homeostatic cell division. Naive T-cell maintenance is known to involve homeostatic cytokines such as interleukin-7 (IL-7). It remains to be investigated what role this cytokine has in the homeostasis of naive CD4(+) T-cell subsets defined by CD31 expression. We provide evidence that IL-7 exerts a preferential proliferative effect on CD31(+) naive CD4(+) T cells from adult peripheral blood compared with the CD31(-) subset. IL-7-driven proliferation did not result in loss of CD31 expression, suggesting that CD31(+) naive CD4(+) T cells can undergo cytokine-driven homeostatic proliferation while preserving CD31. Furthermore, IL-7 sustained or increased CD31 expression even in nonproliferating cells. Both proliferation and CD31 maintenance were dependent on the activation of phosphoinositide 3-kinase (PI3K) signaling. Taken together, our data suggest that during adulthood CD31(+) naive CD4(+) T cells are maintained by IL-7 and that IL-7-based therapies may exert a preferential effect on this population.