Immune Activation and CD8+ T-Cell Differentiation towards Senescence in HIV-1 Infection

Papagno, Laura; Spina, Celsa A.; Marchant, Arnaud; Salio, Mariolina; Rufer, Nathalie; Little, Susan J.; Dong, Tao; Chesney, Gillian; Waters, Anele; Easterbrook, Philippa; Dunbar, P. Rod; Shepherd, Dawn; Cerundolo, Vincenzo; Emery, Vincent C.; Griffiths, Paul; Conlon, Christopher P.; McMichael, Andrew J.; Richman, Douglas D.; Rowland‐Jones, Sarah; Appay, Victor

doi:10.1371/journal.pbio.0020020

Cited by 389 publications

(336 citation statements)

References 69 publications

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“…Immune activation has been demonstrated to play a critical role in HIV disease progression and is known to influence T cell differentiation [8,9,48,49] and AICD [1]. All of these factors have key roles in regulation of the delicate T cell balance.…”

Section: Discussionmentioning

confidence: 99%

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

et al. 2006

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Many factors can influence the rate of HIV disease progression, including those that maintain T cell homeostasis. One key homeostatic regulator is the IL‐7 receptor (IL‐7R). Previous studies have shown IL‐7R expression levels decrease in HIV infection, but effects on memory subtypes, CD4+ T cells, and cell function have not been explored. The present study examined the expression of the IL‐7Rα chain on naïve and memory T lymphocyte subsets of both HIV‐positive and HIV‐negative individuals from Nairobi, Kenya to assess the role of IL‐7Rα in HIV disease. Expression of IL‐7Rα was significantly reduced in all CD4+ and CD8+ T cell subsets in HIV‐positive individuals. This reduction was further enhanced in those with advanced HIV progression. Expression of IL‐7Rα was inversely correlated to immune activation, and apoptosis, and was positively correlated with CD4 count in both bivariate and multivariate analysis. Expression of IL‐7Rα did not correlate with HIV viral loads, indicating the elevated immune activation seen in HIV‐infected individuals may be impacting expression of IL‐7Rα, independent of viral loads. Signaling via the IL‐7R is essential for T cell homeostasis and maintenance of T cell memory. Reduction of this receptor may contribute to the homeostatic disruption seen in HIV.

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Section: Discussionmentioning

confidence: 99%

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

et al. 2006

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“…The functional profile of the CXCR5 + CD8 T cells is not consistent with a classical killer function, but rather with a cytokine-producing effector memory phenotype. Furthermore, these cells consistently express the activation marker CD69, as well as both CD27 and CD28, indicating that they are in an early stage of differentiation [33]. The observation that CXCR5 + CD8 T cells are absent from cord blood, together with their CD45RO + CCR5 + CD7 low phenotype in adult blood, indicate that this subset of CD8 T cells arises in response to antigens encountered after birth.…”

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confidence: 92%

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

et al. 2007

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Naive and central memory CD8 T cells use CCR7 to recirculate through T cell zones of secondary lymphoid organs where they can encounter antigen. Here we describe a subset of human CD8 T cells expressing CXCR5 which enables homing in response to CXCL13 produced within B cell follicles. CXCR5 + CD8 T cells were found in tonsil B cell follicles, and isolated cells migrated towards CXCL13 in vitro. They expressed CD27, CD28, CD45RO, CD69, and were CD7 low , and produced IFN-c and granzyme A but lacked perforin, a functional profile suggesting that these cells are early effector memory cells in the context of contemporary T cell differentiation models. Receptors important in the interaction with B cells, including CD70, OX40 and ICOS, were induced upon activation, and CXCR5 + CD8 T cells could to some extent support survival and IgG production in tonsil B cells. Furthermore, CXCR5 + CD8 T cells expressed CCR5 but no CCR7, suggesting a migration pattern distinct from that of follicular CD4 T cells. The finding that a subset of early effector memory CD8 T cells use CXCR5 to locate to B cell follicles indicates that MHC class I-restricted CD8 T cells are part of the follicular T cell population. IntroductionCD8 T cells are lymphocytes of the adaptive immune system which recognize viral and bacterial peptides presented by MHC class I molecules and are indispensable in the control of many intracellular infections [1]. When appropriately stimulated by antigen presented by dendritic cells (DC) in secondary lymphoid tissues, they proliferate vigorously, become effector cells, and upon resolution of infection a small population of antigen-specific CD8 T cells are maintained as long-lived memory cells [2][3][4]. A primary effector mechanism of CD8 T cells is the killing of infected cells via the targeted release of the lytic effector molecules perforin and granzymes, and via expression of death receptors. However, there is significant functional heterogeneity in CD8 T cells and they are also efficient in producing anti-viral and pro-inflammatory cytokines [5][6][7][8]. The effector mechanisms used may depend on the pathogen and on the type of cell or tissue that is infected [8].CD8 T cell responses involve the differentiation of naive T cells into distinct types of effector and memory cells [2, 3,9]. One approach to analyse a T cell response is to examine the expression of receptors that mediate homing of T cells, such as CD62L, which binds to glycosylation-dependent cell adhesion molecule 1 on [4,20,21]. CXCR5 is a chemokine receptor which is expressed on all B cells and on specialized subsets of DC and T cells [22]. It has only one known ligand, the chemokine CXCL13, mainly produced by stromal cells and follicular DC within B cell follicles [23][24][25]. CXCR5 + CD4 T cells, known as follicular homing T helper cells, are found in B cell follicles and contribute to the generation of effective humoral immune responses by supporting antibody production and isotype class switching [26,27]. However, some of the processes and mec...

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“…Continuous HIV replication provokes the gradual loss of CD8þ T cell functions associated with the expression of negative regulatory molecules, such as PD-1 [117]. In addition to progressive CD8þ T cell exhaustion, HIV infection is characterized by a skewed distribution of HIV-specific CD8þ T cells with low frequencies of effector cells that may be especially prone to apoptosis [118,119].…”

Section: (B) Adaptive Cellular Responses (I) Cd8þ T Cell Responsesmentioning

confidence: 99%

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

Sáez‐Cirión

Jacquelin

Barré‐Sinoussi

et al. 2014

Phil. Trans. R. Soc. B

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International audienceHIV research has made rapid progress and led to remarkable achievements in recent decades, the most important of which are combination antiretroviral therapies (cART). However, in the absence of a vaccine, the pandemic continues, and additional strategies are needed. The 'towards an HIV cure' initiative aims to eradicate HIV or at least bring about a lasting remission of infection during which the host can control viral replication in the absence of cART. Cases of spontaneous and treatment-induced control of infection offer substantial hope. Here, we describe the scientific knowledge that is lacking, and the priorities that have been established for research into a cure. We discuss in detail the immunological lessons that can be learned by studying natural human and animal models of protection and spontaneous control of viraemia or of disease progression. In particular, we describe the insights we have gained into the immune mechanisms of virus control, the impact of early virus-host interactions and why chronic inflammation, a hallmark of HIV infection, is an obstacle to a cure. Finally, we enumerate current interventions aimed towards improving the host immune response

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Immune Activation and CD8+ T-Cell Differentiation towards Senescence in HIV-1 Infection

Cited by 389 publications

References 69 publications

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

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Immune Activation and CD8+ T-Cell Differentiation towards Senescence in HIV-1 Infection

Cited by 389 publications

References 69 publications

IL‐7Rα expression on CD4+ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7Rα expression on CD4+ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

CXCR5+ CCR7– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

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IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

IL‐7Rα expression on CD4⁺ T lymphocytes decreases with HIV disease progression and inversely correlates with immune activation

CXCR5⁺ CCR7^– CD8 T cells are early effector memory cells that infiltrate tonsil B cell follicles