FM-LIC - Artigos em Revistas Internacionais
URI permanente para esta coleção:
Navegar
Entradas recentes
- Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the peripheryPublication . Paiva, Ricardo S.; Lino, Andreia C.; Bergman, Marie-Louise; Caramalho, Íris; Sousa, Ana E.; Zelenay, Santiago; Demengeot, JocelyneMost Forkhead box P3(+) (Foxp3(+)) CD4 regulatory T cell (Treg) precursors are newly formed thymocytes that acquire Foxp3 expression on antigen encounter in the thymus. Differentiation of Treg, however, can also occur in the periphery. What limits this second layer of self- and nonself-reactive Treg production in physiological conditions remains to be understood. In this work, we tested the hypothesis that, similarly to thymic Treg, the precursors of peripheral Treg are immature T cells. We show that CD4(+)CD8(-)Foxp3(-) thymocytes and recent thymic emigrants (RTEs), contrarily to peripheral naïve mature cells, efficiently differentiate into Treg on transfer into lymphopenic mice. By varying donor and recipient mice and conducting ex vivo assays, we document that the preferential conversion of newly formed T cells does not require intrathymic preactivation, is cell-intrinsic, and correlates with low and high sensitivity to natural inhibitors and inducers of Foxp3 expression, such as IL-6, T-cell receptor triggering, and TGF-β. Finally, ex vivo analysis of human thymocytes and peripheral blood T cells revealed that human RTE and newly developed T cells share an increased potential to acquire a FOXP3(bright)CD25(high) Treg phenotype. Our findings indicating that RTEs are the precursors of Tregs differentiated in the periphery should guide the design of Treg-based therapies.
- Regulatory T-cell development in the human thymusPublication . Caramalho, Íris; Nunes-Cabaço, Helena; Foxall, Russell B.; Sousa, Ana E.The thymus generates a lineage-committed subset of regulatory T-cells (Tregs), best identified by the expression of the transcription factor FOXP3. The development of thymus-derived Tregs is known to require high-avidity interaction with MHC-self peptides leading to the generation of self-reactive Tregs fundamental for the maintenance of self-tolerance. Notwithstanding their crucial role in the control of immune responses, human thymic Treg differentiation remains poorly understood. In this mini-review, we will focus on the developmental stages at which Treg lineage commitment occurs, and their spatial localization in the human thymus, reviewing the molecular requirements, including T-cell receptor and cytokine signaling, as well as the cellular interactions involved. An overview of the impact of described thymic defects on the Treg compartment will be provided, illustrating the importance of these in vivo models to investigate human Treg development.
- Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signalingPublication . Ribot, Julie C.; Ribeiro, Sérgio T.; Correia, Daniel V.; Sousa, Ana E.; Silva-Santos, BrunoCytotoxicity and IFN-γ production by human γδ T cells underlie their potent antitumor functions. However, it remains unclear where and how human γδ T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine γδ T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo-isolated γδ thymocytes produced negligible IFN-γ and lacked cytolytic activity against leukemia cells. However, these properties were selectively acquired upon stimulation with IL-2 or IL-15, but not IL-4 or IL-7. Unexpectedly, TCR activation was dispensable for these stages of functional differentiation. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of γδ T cells in cancer immunotherapy.
- TACI deficiency enhances antibody avidity and clearance of an intestinal pathogenPublication . Tsuji, Shoichiro; Stein, Lucas; Kamada, Nobuhiko; Nuñez, Gabriel; Bram, Richard; Vallance, Bruce A.; Sousa, Ana E.; Platt, Jeffrey L.; Cascalho, MariliaThe transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) controls differentiation of long-lived plasma cells, and almost 10% of individuals with common variable immunodeficiency (CVID) express either the C104R or A181E variants of TACI. These variants impair TACI function, and TACI-deficient mice exhibit a CVID-like disease. However, 1%-2% of normal individuals harbor the C140R or A181E TACI variants and have no outward signs of CVID, and it is not clear why TACI deficiency in this group does not cause disease. Here, we determined that TACI-deficient mice have low baseline levels of Ig in the blood but retain the ability to mutate Ig-associated genes that encode antigen-specific antibodies. The antigen-specific antibodies in TACI-deficient mice were produced in bursts and had higher avidity than those of WT animals. Moreover, mice lacking TACI were able to clear Citrobacter rodentium, a model pathogen for severe human enteritis, more rapidly than did WT mice. These findings suggest that the high prevalence of TACI deficiency in humans might reflect enhanced host defense against enteritis, which is more severe in those with acquired or inherited immunodeficiencies.
- Thymic stromal alterations and genetic disorders of immune systemPublication . Pignata, Claudio; D'Assante, Roberta; Sousa, Ana E.
- CD4+ recent thymic emigrants are infected by HIV in vivo, implication for pathogenesisPublication . Fabre-Mersseman, Véronique; Dutrieux, Jacques; Louise, Anne; Rozlan, Sandra; Lamine, Aurélia; Parker, Raphaëlle; Rancez, Magali; Nunes-Cabaço, Helena; Sousa, Ana E.; Lambotte, Olivier; Cheynier, RémiOBJECTIVE: The contribution of naive CD4+ T cells to the pool of HIV-infected cells remains poorly described. This study aimed at evaluating HIV infection in naive T-cell subsets in viremic and HAART-treated patients, together with various parameters implicated in naive T-cell homeostasis, in order to better understand infection in these subsets. DESIGN AND METHODS: HIV provirus was quantified in various FACS-sorted CD4/CD8 T-cell subsets [recent thymic emigrants (RTEs), non-RTE naives and memory T cells] purified from peripheral blood cells of untreated viremic and HAART-treated aviremic HIV-infected patients. HIV proviral DNA was quantified using a highly sensitive real-time PCR assay allowing detection of one HIV copy in 10⁵ cells. Intrathymic precursor T-cell proliferation and circulating T-cell cycling were, respectively, evaluated through measurement of the sj/βTREC ratio (signal joint T-Cell Receptor Excision Circle frequency divided by DβJβTREC frequency) and Ki-67 expression. Plasma interleukin (IL)-7 concentrations were measured by ELISA. RESULTS: RTEs and non-RTEs were equally HIV infected. Altogether, naive CD4+ T cells represented 0.24%-60% of the infected cells. In contrast, HIV DNA was undetectable in naive CD8+ T cells. RTE infection rate directly correlated with IL-7 plasma levels (r = 0.607, P = 0.0035) but was independent from plasma viral load, peripheral T-cell cycling and intrathymic precursor T-cell proliferation. CONCLUSION: We demonstrated that RTEs are effectively HIV infected. The similar infection rate observed in RTEs and other naive T cells, its relationship with plasma IL-7 levels, together with the lack of correlation between RTE infection and either thymic or peripheral proliferation, strongly suggests that RTE infection occurs either late during thymopoiesis or early on during their extrathymic maturation.
- 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.
- Thymic HIV-2 infection uncovers posttranscriptional control of viral replication in human thymocytesPublication . Nunes-Cabaço, H.; Matoso, P.; Foxall, R. B.; Tendeiro, R.; Pires, A. R.; Carvalho, Tânia; Pinheiro, A. I.; Soares, R. S.; Sousa, A. E.A unique HIV-host equilibrium exists in untreated HIV-2-infected individuals. This equilibrium is characterized by low to undetectable levels of viremia throughout the disease course, despite the establishment of disseminated HIV-2 reservoirs at levels comparable to those observed in untreated HIV-1 infection. Although the clinical spectrum is similar in the two infections, HIV-2 infection is associated with a much lower rate of CD4 T-cell decline and has a limited impact on the mortality of infected adults. Here we investigated HIV-2 infection of the human thymus, the primary organ for T-cell production. Human thymic tissue and suspensions of total or purified CD4 single-positive thymocytes were infected with HIV-2 or HIV-1 primary isolates using either CCR5 or CXCR4 coreceptors. We found that HIV-2 infected both thymic organ cultures and thymocyte suspensions, as attested to by the total HIV DNA and cell-associated viral mRNA levels. Nevertheless, thymocytes featured reduced levels of intracellular Gag viral protein, irrespective of HIV-2 coreceptor tropism and cell differentiation stage, in agreement with the low viral load in culture supernatants. Our data show that HIV-2 is able to infect the human thymus, but the HIV-2 replication cycle in thymocytes is impaired, providing a new model to identify therapeutic targets for viral replication control. IMPORTANCE: HIV-1 infects the thymus, leading to a decrease in CD4 T-cell production that contributes to the characteristic CD4 T-cell loss. HIV-2 infection is associated with a very low rate of progression to AIDS and is therefore considered a unique naturally occurring model of attenuated HIV disease. HIV-2-infected individuals feature low to undetectable plasma viral loads, in spite of the numbers of circulating infected T cells being similar to those found in patients infected with HIV-1. We assessed, for the first time, the direct impact of HIV-2 infection on the human thymus. We show that HIV-2 is able to infect the thymus but that the HIV-2 replication cycle in thymocytes is impaired. We propose that this system will be important to devise immunotherapies that target viral production, aiding the design of future therapeutic strategies for HIV control.
- Low CD4 T-cell counts despite low levels of circulating HIV : insights from the comparison of HIV-1 infected patients with a discordant response to antiretroviral therapy to patients with untreated advanced HIV-2 diseasePublication . Albuquerque, A. S.; Foxall, R. B.; Cortesão, C. S.; Soares, R. S.; Doroana, M.; Ribeiro, A.; Lucas, M.; Antunes, F.; Victorino, R. M.; Sousa, A. E.A significant proportion of HIV-1+ patients with suppression of viremia under antiretroviral therapy fail to recover CD4(+) T-cell counts (ART-Discordants). Similarly, untreated HIV-2+ patients can also exhibit major CD4 depletion in spite of undetectable viremia. We characterize here the immunological disturbances associated with major CD4-lymphopenia in these two scenarios as compared to untreated viremic HIV-1+ patients with similar CD4-lymphopenia and HIV-1+ patients with successful immunological and virological responses under ART. Low CD4 counts were associated with major naive CD4 and CD8 depletion, irrespective of type of infection or ART-exposure. However, ART-Discordants exhibited lower levels of T-cell activation as compared to both untreated HIV-2 and HIV-1 cohorts, and a less marked increase in circulating IL-7 despite similar CD4 depletion. Nevertheless, ART-Discordants showed a preserved Bcl-2 expression, suggesting increased IL-7 consumption, which in conjunction with the relatively lower T-cell activation may contribute to their CD4 count stability and low rate of opportunistic infections.
- Attenuated vaccines for AIDS?Publication . Victorino, R. M.; Sousa, A. E.