Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors

Ribeiro-dos-Santos, Patricia; Turnbull, Emma L.; Monteiro, Marta; Legrand, Agnès; Conrod, Karen; Baalwa, Joshua; Pellegrino, Pierre; Shaw, George M.; Williams, Ian; Borrow, Persephone; Rocha, Bénédita

doi:10.1182/blood-2011-12-395186

Cited by 21 publications

(22 citation statements)

References 50 publications

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“…Nevertheless, given that recent studies have shown that T-bet expression is co-localized both in the nucleus and cytoplasm [50], our results further suggest that HIV-specific CD8+ T cells in HIV chronic progressors might have high abundance of T-bet in the cytoplasm, leading to the inability to repress the expression of inhibitory receptors and induce cytolytic functions. However, a recent study by Ribeiro-dos-Santos et al concluded that loss of cytolytic potential of HIV-specific CD8+ T cells was a consequence of both T-bet and Eomes down-regulation in the chronic phase of HIV infection [51]. The discrepancies between this study and our results here are most likely due to the use of different techniques to observe the levels of transcription factors.…”

Section: Discussioncontrasting

confidence: 97%

T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection

et al. 2014

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CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation.

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Section: Discussioncontrasting

confidence: 97%

T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection

et al. 2014

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“…The CD56+ CD8 T cells expressing T-bet mostly co-expressed EOMES (Figure 3A). In contrast, a large proportion of CD56- cells were negative for both T-bet and EOMES (Figure 3A), a phenotype predicted to have reduced lytic effector function [23], [24]. Recently, HIV infection was shown to downregulate both of these transcription factors in CD8 T cells [23].…”

Section: Resultsmentioning

confidence: 98%

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

Poonia

Pauza

2014

PLoS ONE

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Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic effector function that is needed to eradicate the viral reservoir. Better understanding of the phenotype and function of circulating CD8 cells in HIV patients will contribute to new targeted therapies directed at increasing CD8 T cell lytic effector function and destruction of the viral reservoir. We show that CD8 T cells from ART treated patients had sharply reduced expression of CD56 (neural cell adhesion molecule-1), a marker associated with cytolytic function whereas elite patients who control HIV in the absence of ART had CD56+ CD8 T cell levels similar to uninfected controls. The CD56+ CD8 T cells had higher perforin upregulation as well as degranulation following stimulation with HIV gag peptides compared with CD56 negative CD8 T cells. Elite patients had the highest frequencies of perforin producing CD56+ CD8 T cells among all HIV+ groups. In patients receiving ART we noted high levels of the exhaustion marker TIM-3 on CD56+ CD8 T cells, implying that defective effector function was related to immune exhaustion. CD56+ CD8 T cells from elite or treated HIV patients responded to PMA plus ionomycin stimulation, and expressed transcription factors T-bet and EOMES at levels similar to uninfected controls. Consequently, the lytic effector defect in chronic HIV disease is due to immune exhaustion and quantitative loss of CD56+ CD8 T cells and this defect is not repaired in patients where viremia is suppressed and CD4 T cells are recovered after ART.Reconstituting the cytotoxic CD56+ subset of CD8+ T cells through new interventions might improve the lytic effector capacity and contribute to reducing the viral reservoir. Our initial studies indicate that IL-15 treatment partly reverses the CD56 defect, implying that myeloid cell defects could be targeted for immune therapy during chronic HIV disease.

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“…Recent studies found that another transcription factor, Eomes, regulates IFN-γ production by T-cells in intracellular infections (28), but it has both positive and negative regulatory effects depending on the infection (29, 30). The role of Eomes in Mtb infection is not known.…”

Section: Resultsmentioning

confidence: 99%

IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice

Cheekatla

Tripathi

Venkatasubramanian

et al. 2017

The Journal of Immunology

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In the current study we determined the role of IL-21 receptor signaling in Mycobacterium tuberculosis (Mtb) infection, using IL-21 receptor knockout (IL-21R KO) mice. Fifty percent of Mtb H37Rv infected IL-21R KO mice died in six months compared to no deaths in infected wild type (WT) mice. Mtb infected IL-21R KO mice had enhanced bacterial burden and reduced infiltration of antigen specific T-cells in lungs compared to Mtb infected WT mice. Antigen specific T-cells from the lungs of Mtb infected IL-21R KO mice had increased expression of T-cell inhibitory receptors, reduced expression of chemokine receptors, proliferated less and produced less IFN- γ, compared to antigen specific T cells from the lungs of Mtb infected WT mice. T cells from Mtb infected IL-21R KO mice were unable to induce optimal macrophage responses to Mtb. This may be due to a decrease in the antigen specific T cell population. We also found that IL-21R signaling is associated with reduced expression of a transcriptional factor Eomesodermin (Eomes) and enhanced functional capacity of antigen specific T-cells of Mtb infected mice. The sum of our findings suggests that IL-21 receptor signaling is essential for the optimal control of Mtb infection.

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Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors

Cited by 21 publications

References 50 publications

T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection

T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice

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