Memory CD8 T-Cell Differentiation during Viral Infection

Wherry, E. John; Ahmed, Rafi

doi:10.1128/jvi.78.11.5535-5545.2004

Cited by 774 publications

(814 citation statements)

References 144 publications

(198 reference statements)

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“…T he CD8 ϩ T cell is a critical component of the immune system's response to infectious agents and tumors (1)(2)(3). Activation of naive T cells begins when the TCR encounters cognate Ag presented by MHC proteins on the surface of APCs.…”

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confidence: 99%

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The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

Michalek

Nelson

Holbrook

et al. 2007

The Journal of Immunology

101

102

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Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in mediating cellular responses. We have examined the importance of reversible cysteine sulfenic acid formation in naive CD8+ T cell activation and proliferation. We observed that, within minutes of T cell activation, naive CD8+ T cells increased ROI levels in a manner dependent upon Ag concentration. Increased ROI resulted in elevated levels of cysteine sulfenic acid in the total proteome. Analysis of specific proteins revealed that the protein tyrosine phosphatases SHP-1 and SHP-2, as well as actin, underwent increased sulfenic acid modification following stimulation. To examine the contribution of reversible cysteine sulfenic acid formation to T cell activation, increasing concentrations of 5,5-dimethyl-1,3-cyclohexanedione (dimedone), which covalently binds to cysteine sulfenic acid, were added to cultures. Subsequent experiments demonstrated that the reversible formation of cysteine sulfenic acid was critical for ERK1/2 phosphorylation, calcium flux, cell growth, and proliferation of naive CD8+ and CD4+ T cells. We also found that TNF-α production by effector and memory CD8+ T cells was more sensitive to the inhibition of reversible cysteine sulfenic acid formation than IFN-γ. Together, these results demonstrate that reversible cysteine sulfenic acid formation is an important regulatory mechanism by which CD8+ T cells are able to modulate signaling, proliferation, and function.

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confidence: 99%

“…The critical role of reactive oxygen intermediates (ROI) 3 in innate immune responses has been well documented. Upon activation, phagocytic cells such as neutrophils and macrophages increase the production of O 2 .…”

mentioning

confidence: 99%

The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

Michalek

Nelson

Holbrook

et al. 2007

The Journal of Immunology

101

102

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“…To better characterize these peripheral CD8 1 T cells, we examined their cell-surface markers in the naïve state, their ability to produce cytokines upon activation, and their TCR repertoire. Compared to the activated T cells, naïve T cells express lower levels of CD44, CD11a, Ly6C, CD69 and integrin a4b7 and higher levels of CD62L and CD127 (IL-27Ra) [15]. We found that CD8 1 T cells from the spleen and MLN of Tg mice exhibit a profile that is similar to that of B6 mice for each of these surface markers (Fig.…”

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confidence: 57%

“…Development of CD8 1 T cells in thymus starts with the differentiation of CD4 À CD8 À double negative (DN) precursor T cells into CD4 1 CD8 1 double positive (DP) cells, then into CD4 1 CD8b lo transition cells, and finally maturation into CD8 1 single positive (SP) cells [11][12][13][14]. After emigration into periphery, these CD8 1 T cells, in response to viral infection, can be activated by viral antigens and expanded as effector cytotoxic T lymphocytes, which are capable of eliminating the virus-infected cells [15]. The roles played by the interactions between CD8 proteins and MHCI in thymic differentiation and effector functions are not all clear.…”

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confidence: 99%

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An active CD8α/pMHCI interaction is required for CD8 single positive thymocyte differentiation

et al. 2010

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Recognition of viral antigenic peptides bound to major histocompatibility complex class I molecules (MHCI) by TCR is critical for initiating the responses of CD8 1 T cells that ultimately lead to elimination of virus-infected cells. This antigen recognition is enhanced by the CD8 coreceptor through its interaction with the peptide-MHCI complexes (pMHCI). Mouse CD8ab can form two different complexes with pMHCI via either the CD8a-or CD8b-dominated interaction. To understand the functional significance of these complexes in vivo, we generated Tg mice carrying a variant CD8ab (CD8a m3 b) capable of forming only the CD8b-dominated CD8ab/pMHCI complex. These mice show sub-optimal thymic differentiation with reduced populations of CD8 1 single-positive thymocytes. Tg CD8 1 T cells exhibit a compromised developmental capacity when competing with CD8 1 T cells from B6 mice in mixed bone marrow chimera experiments. However, once these CD8 1 T cells have emigrated to the peripheral lymphoid organs, they exhibit normal effector function against viral infection. Our observations indicate that, in addition to the CD8 activity conferred by CD8b-dominated CD8ab/pMHCI complexes, full thymocyte differentiation requires additional coreceptor activities conferred by CD8aa and/or CD8ab with CD8a-dominated CD8/pMHCI complexes.Key words: CD8/pMHCI interaction . Coreceptor functions . T-cell differentiation .Viral infection . Tg mice Supporting Information available online IntroductionThe recognition of peptide antigen loaded on the major histocompatibility complex I (pMHCI) displayed on APC by the TCR is greatly enhanced by the simultaneous engagement of pMHCI with CD8 proteins on class I restricted CD8 1 T lymphocytes [1][2][3]. Such enhancement of antigen recognition is critical not only for triggering the activation of CD8 1 T cells but also for the differentiation of CD8 1 T cells in thymus [4][5][6][7][8][9][10]. Development of CD8 1 T cells in thymus starts with the differentiation of CD4 À CD8 À double negative (DN) precursor T cells into CD4 1 CD8 1 double positive (DP) cells, then into CD4 1 CD8b lo transition cells, and finally maturation into CD8 1 single positive (SP) cells [11][12][13][14]. After emigration into periphery, these CD8 1 T cells, in response to viral infection, can be activated by viral antigens and expanded as effector cytotoxic T lymphocytes, 836which are capable of eliminating the virus-infected cells [15]. The roles played by the interactions between CD8 proteins and MHCI in thymic differentiation and effector functions are not all clear.CD8 proteins are encoded by two genes, CD8a and CD8b, and expressed on the cell surface as homodimeric CD8aa and heterodimeric CD8ab [16]. Although both CD8aa and CD8ab bind to the classic MHCI molecules and function as coreceptors to enhance recognition of peptide antigens by TCR, CD8ab is apparently more efficient than CD8aa [17][18][19]. Surface expression of CD8b requires its heterodimerization with CD8a [20] and, consequently, no cellsurface CD8b protein can be de...

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Immune Evasion by Viruses

Simmons

Willberg

Klenerman

2013

Encyclopedia of Life Sciences

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When a virus infects a host, a complex immune response develops to eliminate the invading pathogen. Viruses, in turn, have evolved a profusion of strategies to escape from the immune system. Mechanisms of viral evasion can be separated into those that occur at the cellular level and those that are important at the systemic level. Viruses can avoid detection by both innate and adaptive immune responses. Pattern recognition receptors in infected cells, interferons, dendritic cells, T cell receptors and antibodies are all targets of viral evasion proteins. Viruses can express proteins that directly interfere with host processes or mimic host proteins and compete to bind specific receptors. Pathogens are also able to directly deplete immune cells, and prevent their recruitment to the site of infection. In a state of latency, viruses remain dormant and undetectable in host cells. The diversity of these mechanisms has allowed us to dissect the immune system further and understand how viruses persist despite such a strong counterattack by the immune system. Key Concepts: Viruses have evolved a plethora of mechanisms to inhibit every step of the innate and adaptive immune responses. Viruses avoid detection by pattern recognition receptors, T cell receptors and antibodies by modifying the ligands for these receptors. Different viruses target every stage of antigen processing and presentation by MHC molecules, thus inhibiting recognition by T cells. Interferons, cytokines and chemokines are mimicked or blocked by viral proteins to prevent the efficient development of an immune response. Through repression of their replication, viruses are able to enter latency and remain dormant inside the cell, remaining undetectable.

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Memory CD8 T-Cell Differentiation during Viral Infection

Cited by 774 publications

References 144 publications

The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

The Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function

An active CD8α/pMHCI interaction is required for CD8 single positive thymocyte differentiation

Immune Evasion by Viruses

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