| 1. |
- Buggert, Marcus, et al.
(författare)
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Limited immune surveillance in lymphoid tissue by cytolytic CD4+ T cells during health and HIV disease
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 14:4
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Tidskriftsartikel (refereegranskat)abstract
- CD4+ T cells subsets have a wide range of important helper and regulatory functions in the immune system. Several studies have specifically suggested that circulating effector CD4+ T cells may play a direct role in control of HIV replication through cytolytic activity or autocrine β-chemokine production. However, it remains unclear whether effector CD4+ T cells expressing cytolytic molecules and β-chemokines are present within lymph nodes (LNs), a major site of HIV replication. Here, we report that expression of β-chemokines and cytolytic molecules are enriched within a CD4+ T cell population with high levels of the T-box transcription factors T-bet and eomesodermin (Eomes). This effector population is predominately found in peripheral blood and is limited in LNs regardless of HIV infection or treatment status. As a result, CD4+ T cells generally lack effector functions in LNs, including cytolytic capacity and IFNγ and β-chemokine expression, even in HIV elite controllers and during acute/early HIV infection. While we do find the presence of degranulating CD4+ T cells in LNs, these cells do not bear functional or transcriptional effector T cell properties and are inherently poor to form stable immunological synapses compared to their peripheral blood counterparts. We demonstrate that CD4+ T cell cytolytic function, phenotype, and programming in the peripheral blood is dissociated from those characteristics found in lymphoid tissues. Together, these data challenge our current models based on blood and suggest spatially and temporally dissociated mechanisms of viral control in lymphoid tissues.
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| 2. |
- Sekine, Takuya, et al.
(författare)
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TOX is expressed by exhausted and polyfunctional human effector memory CD8(+) T cells
- 2020
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Ingår i: Science immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 5:49
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Tidskriftsartikel (refereegranskat)abstract
- CD8(+) T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8(+) T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8(+) T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this study, we mapped the expression of TOX and TCF-1 as a function of differentiation and specificity in the human CD8(+) T cell landscape. Here, we demonstrate that circulating TOX+ CD8(+) T cells exist in most humans, but that TOX is not exclusively associated with exhaustion. Effector memory CD8(+) T cells generally expressed TOX, whereas naive and early-differentiated memory CD8(+) T cells generally expressed TCF-1. Cytolytic gene and protein expression signatures were also defined by the expression of TOX. In the context of a relentless immune challenge, exhausted HIV-specific CD8(+) T cells commonly expressed TOX, often in clusters with various activation markers and inhibitory receptors, and expressed less TCF-1. However, polyfunctional memory CD8(+) T cells specific for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) also expressed TOX, either with or without TCF-1. A similar phenotype was observed among HIV-specific CD8(+) T cells from individuals who maintained exceptional immune control of viral replication. Collectively, these data demonstrate that TOX is expressed by most circulating effector memory CD8(+) T cell subsets and not exclusively linked to exhaustion.
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| 3. |
- Buggert, Marcus, et al.
(författare)
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CD4+ T cells with an activated and exhausted phenotype distinguish immunodeficiency during aviremic HIV-2 infection
- 2016
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Ingår i: AIDS. - 0269-9370. ; 30:16, s. 2415-2426
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:: HIV-2 represents an attenuated form of HIV, where many infected individuals remain “aviremic” without antiretroviral therapy (ART). However, aviremic HIV-2 disease progression exits, and in the current study we therefore aimed to examine if specific pathological characteristics of CD4+ T cells are linked to such outcome. DESIGN:: HIV-seronegative (n=25), HIV-1 (n?=?33), HIV-2 (n?=?39, of whom 26 were aviremic), and HIV-1/2 dually (HIV-D) (n?=?13) infected subjects were enrolled from an occupational cohort in Guinea-Bissau. METHODS:: CD4+ T cell differentiation, activation, exhaustion, senescence, and transcription factors were assessed by polychromatic flow cytometry. Multidimensional clustering bioinformatic tools were used to identify CD4+ T cell subpopulations linked to infection type and disease stage. RESULTS:: HIV-2-infected individuals had early- and late-differentiated CD4+ T cell clusters with lower activation (CD38+HLA-DR+) and exhaustion (PD-1) than HIV-1 and HIV-D-infected subjects. We also noted that aviremic HIV-2-infected individuals possessed fewer CD4+ T cells with pathological signs compared to other HIV-infected groups. Still, compared to HIV-seronegatives, aviremic HIV-2-infected subjects had T-bet+ CD4+ T cells that showed elevated immune activation/exhaustion, and particularly the frequencies of PD-1+ cells were associated with suboptimal percentage of CD4+ T cells. CONCLUSIONS:: Increased frequencies of CD4+ T cells with an activated/exhausted phenotype correlate with exacerbated immunodeficiency in aviremic HIV-2-infected individuals. Thus, these findings encourage studies on the introduction of ART also to individuals with aviremic HIV-2 infection.
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| 4. |
- Buggert, Marcus, et al.
(författare)
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T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+ T Cells in HIV Infection.
- 2014
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- 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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