Transient Loss of MHC Class I Tetramer Binding after CD8+ T Cell Activation Reflects Altered T Cell Effector Function

Drake, Donald R.; Ream, Rebecca M.; Lawrence, Christopher W.; Braciale, Thomas J.

doi:10.4049/jimmunol.175.3.1507

Cited by 34 publications

(35 citation statements)

References 34 publications

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“…Downregulation of the TCR following stimulation and reorganization of the TCR and CD8 on the cell surface can both lead to decreased tetramer binding (11,12). Consequently, we were unable to stain with tetramer and examine effector functions of virus-specific CD8 T cells within the same assay.…”

Section: Altered Cytokine Production By Virus-specific Cd8 T Cells Inmentioning

confidence: 99%

Regulation of Cytokine Production by Virus-Specific CD8 T Cells in the Lungs

Fulton

Olson

Varga

2008

J Virol

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Inflammation and the elimination of infected host cells during an immune response often cause local tissue injury and immunopathology, which can disrupt the normal functions of tissues such as the lung. Here, we show that both virus-induced inflammation and the host tissue environment combine to influence the capacity of virus-specific CD4 and CD8 T cells to produce cytokines in various tissues. Decreased production of cytokines, such as IFN-␥ and TNF-␣, by antigen-specific T cells is more pronounced in peripheral tissues, such as the lung and kidney, than in secondary lymphoid organs, such as the spleen or lymph nodes. We also demonstrate that tissues regulate cytokine production by memory T cells independently of virus infection, as memory T cells that traffic into the lungs of naïve animals exhibit a reduced ability to produce cytokines following direct ex vivo peptide stimulation. Furthermore, we show that cytokine production by antigen-specific memory CD4 and CD8 T cells isolated from the lung parenchyma can be rescued by stimulation with exogenous peptide-pulsed antigen-presenting cells. Our results suggest that the regulation of T-cell cytokine production by peripheral tissues may serve as an important mechanism to prevent immunopathology and preserve normal tissue function.

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Section: Altered Cytokine Production By Virus-specific Cd8 T Cells Inmentioning

confidence: 99%

Regulation of Cytokine Production by Virus-Specific CD8 T Cells in the Lungs

Fulton

Olson

Varga

2008

J Virol

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“…On the other hand, the transcription of cytotoxic effector genes varied: Gzmb and Prf1 peaked early, while Gzma and Fasl were present only in a minority of CD69 ϩ cells, and a significant rise in their expression occurred as they progressed to the CD69 Ϫ stage (for Gzma, P ϭ 0.0001; for Fasl, P ϭ 0.002). Notably, the generation of Il2 mRNA was found rarely in ex vivo P14 cells (less than 5% of total cells; data not shown) at any of the stages tested (days 3,4,8,15,30, and 60). The latter finding casts doubt on the physiological significance of reports that TCR Tg effector CD8 cells arising from high precursor frequencies are more likely to secrete IL-2 upon in vitro stimulation (2).…”

Section: Vol 83 2009 Cd8 Differentiation Patterns During Lcmv Infecmentioning

confidence: 99%

Epitope Specificity and Relative Clonal Abundance Do Not Affect CD8 Differentiation Patterns during Lymphocytic Choriomeningitis Virus Infection

Munitić

Decaluwe

Evaristo

et al. 2009

J Virol

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To evaluate the impact of immunodominance on CD8 T-cell properties, we compared the functional properties of dominant and subdominant populations in the response to lymphocytic choriomeningitis virus (LCMV). To improve functional discrimination, in addition to the usual tests of phenotype and function, we used a sensitive technique that allows the screening of all CD8 effector genes simultaneously in single cells. Surprisingly, these methods failed to reveal a major impact of clonal dominance in CD8 properties throughout the response. Aiming to increase clonal dominance, we examined high-frequency transferred P14 T-cell receptor transgenic (TCR Tg) cells. Under these conditions LCMV is cleared faster, and accordingly we found an accelerated response. However, when Tg and endogenous cells were studied in the same mice, where they should be subjected to the same antigen load, they showed overlapping properties, and the presence of P14 cells did not modify endogenous responses to other LCMV epitopes or a perturbed immunodominance hierarchy in the memory phase. Using allotype-labeled Tg cells, we found that during acute infection up to 80% downregulated their TCR and were undetectable by tetramer binding, and that tetramer-negative and tetramer-positive cells had very different features. Since Tg cells are not available to evaluate immune responses in humans and, in many cases, are not available from the mouse, the tetramer-based evaluation of early immune responses in most situations of high viremia may be incomplete and biased.

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“…shows two populations of tetramer-positive cells, one which is tetramer low and positive for L-selectin, IL-2/IL-15␤, IL-7␣, and CCR7, and one which is tetramer high and negative for the markers tested. Transient loss of tetramer binding and TCR/CD8 down-regulation has been observed after T cell activation (43)(44)(45) and could be explained by the asymmetric T cell lymphocyte division after Ag stimulation (46). To determine whether memory T cell precursors generated during primary infection had a central-or effector-memory phenotype and their anatomical distribution, : bone marrow 9.8%, MLN 12.1%, and spleen 7.3%).…”

Section: Generation Of Central-memory Cd8 ϩ T Cells During Virus Persmentioning

confidence: 99%

Memory Generation and Maintenance of CD8+ T Cell Function during Viral Persistence

Cush¹,

Anderson²,

Ravneberg³

et al. 2007

The Journal of Immunology

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During infection with viruses that establish latency, the immune system needs to maintain lifelong control of the infectious agent in the presence of persistent Ag. By using a γ-herpesvirus (γHV) infection model, we demonstrate that a small number of virus-specific central-memory CD8+ T cells develop early during infection, and that virus-specific CD8+ T cells maintain functional and protective capacities during chronic infection despite low-level Ag persistence. During the primary immune response, we show generation of CD8+ memory T cell precursors expressing lymphoid homing molecules (CCR7, L-selectin) and homeostatic cytokine receptors (IL-7α, IL-2/IL-15β). During long-term persistent infection, central-memory cells constitute 20–50% of the virus-specific CD8+ T cell population and maintain the expression of L-selectin, CCR7, and IL-7R molecules. Functional analyses demonstrate that during viral persistence: 1) CD8+ T cells maintain TCR affinity for peptide/MHC complexes, 2) the functional avidity of CD8+ T cells measured as the capacity to produce IFN-γ is preserved intact, and 3) virus-specific CD8+ T cells have in vivo killing capacity. Next, we demonstrate that at 8 mo post-virus inoculation, long-term CD8+ T cells are capable of mediating a protective recall response against the establishment of γHV68 splenic latency. These observations provide evidence that functional CD8+ memory T cells can be generated and maintained during low-load γHV68 persistence.

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Transient Loss of MHC Class I Tetramer Binding after CD8+ T Cell Activation Reflects Altered T Cell Effector Function

Cited by 34 publications

References 34 publications

Regulation of Cytokine Production by Virus-Specific CD8 T Cells in the Lungs

Regulation of Cytokine Production by Virus-Specific CD8 T Cells in the Lungs

Epitope Specificity and Relative Clonal Abundance Do Not Affect CD8 Differentiation Patterns during Lymphocytic Choriomeningitis Virus Infection

Memory Generation and Maintenance of CD8+ T Cell Function during Viral Persistence

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