MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response

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@article{2eda5d4e60154fa79f7417d993e4f6f7,
title = "MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response",
abstract = "Virus-specific CD4(+) T cells are key orchestrators of host responses to viral infection yet, compared with their CD8(+) T cell counterparts, remain poorly characterized at the single cell level. Here we use nine MHC II-epitope peptide tetramers to visualize human CD4(+) T cell responses to Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis (IM), a disease associated with large virus-specific CD8(+) T cell responses. We find that, while not approaching virus-specific CD8(+) T cell expansions in magnitude, activated CD4(+) T cells specific for epitopes in the latent antigen EBNA2 and four lytic cycle antigens are detected at high frequencies in acute IM blood. They then fall rapidly to values typical of life-long virus carriage where most tetramer-positive cells display conventional memory markers but some, unexpectedly, revert to a naive-like phenotype. In contrast CD4(+) T cell responses to EBNA1 epitopes are greatly delayed in IM patients, in line with the well-known but hitherto unexplained delay in EBNA1 IgG antibody responses. We present evidence from an in vitro system that may explain these unusual kinetics. Unlike other EBNAs and lytic cycle proteins, EBNA1 is not naturally released from EBV-infected cells as a source of antigen for CD4(+) T cell priming.",
keywords = "Acute Disease, Antibody Formation, Antigens, Viral, CD4-Positive T-Lymphocytes, Cell Proliferation, Convalescence, Epitopes, Epstein-Barr Virus Infections, Epstein-Barr Virus Nuclear Antigens, Herpesvirus 4, Human, Histocompatibility Antigens Class II, Humans, Immunoglobulin G, Immunologic Memory, Infectious Mononucleosis, Kinetics, Phenotype, Protein Multimerization, Species Specificity, Journal Article, Research Support, Non-U.S. Gov't",
author = "Long, {Heather M} and Chagoury, {Odette L} and Leese, {Alison M} and Ryan, {Gordon B} and Eddie James and Morton, {Laura T} and Abbott, {Rachel J M} and Shereen Sabbah and William Kwok and Rickinson, {Alan B}",
year = "2013",
month = may,
day = "6",
doi = "10.1084/jem.20121437",
language = "English",
volume = "210",
pages = "933--49",
journal = "The Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "5",

}

RIS

TY - JOUR

T1 - MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response

AU - Long, Heather M

AU - Chagoury, Odette L

AU - Leese, Alison M

AU - Ryan, Gordon B

AU - James, Eddie

AU - Morton, Laura T

AU - Abbott, Rachel J M

AU - Sabbah, Shereen

AU - Kwok, William

AU - Rickinson, Alan B

PY - 2013/5/6

Y1 - 2013/5/6

N2 - Virus-specific CD4(+) T cells are key orchestrators of host responses to viral infection yet, compared with their CD8(+) T cell counterparts, remain poorly characterized at the single cell level. Here we use nine MHC II-epitope peptide tetramers to visualize human CD4(+) T cell responses to Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis (IM), a disease associated with large virus-specific CD8(+) T cell responses. We find that, while not approaching virus-specific CD8(+) T cell expansions in magnitude, activated CD4(+) T cells specific for epitopes in the latent antigen EBNA2 and four lytic cycle antigens are detected at high frequencies in acute IM blood. They then fall rapidly to values typical of life-long virus carriage where most tetramer-positive cells display conventional memory markers but some, unexpectedly, revert to a naive-like phenotype. In contrast CD4(+) T cell responses to EBNA1 epitopes are greatly delayed in IM patients, in line with the well-known but hitherto unexplained delay in EBNA1 IgG antibody responses. We present evidence from an in vitro system that may explain these unusual kinetics. Unlike other EBNAs and lytic cycle proteins, EBNA1 is not naturally released from EBV-infected cells as a source of antigen for CD4(+) T cell priming.

AB - Virus-specific CD4(+) T cells are key orchestrators of host responses to viral infection yet, compared with their CD8(+) T cell counterparts, remain poorly characterized at the single cell level. Here we use nine MHC II-epitope peptide tetramers to visualize human CD4(+) T cell responses to Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis (IM), a disease associated with large virus-specific CD8(+) T cell responses. We find that, while not approaching virus-specific CD8(+) T cell expansions in magnitude, activated CD4(+) T cells specific for epitopes in the latent antigen EBNA2 and four lytic cycle antigens are detected at high frequencies in acute IM blood. They then fall rapidly to values typical of life-long virus carriage where most tetramer-positive cells display conventional memory markers but some, unexpectedly, revert to a naive-like phenotype. In contrast CD4(+) T cell responses to EBNA1 epitopes are greatly delayed in IM patients, in line with the well-known but hitherto unexplained delay in EBNA1 IgG antibody responses. We present evidence from an in vitro system that may explain these unusual kinetics. Unlike other EBNAs and lytic cycle proteins, EBNA1 is not naturally released from EBV-infected cells as a source of antigen for CD4(+) T cell priming.

KW - Acute Disease

KW - Antibody Formation

KW - Antigens, Viral

KW - CD4-Positive T-Lymphocytes

KW - Cell Proliferation

KW - Convalescence

KW - Epitopes

KW - Epstein-Barr Virus Infections

KW - Epstein-Barr Virus Nuclear Antigens

KW - Herpesvirus 4, Human

KW - Histocompatibility Antigens Class II

KW - Humans

KW - Immunoglobulin G

KW - Immunologic Memory

KW - Infectious Mononucleosis

KW - Kinetics

KW - Phenotype

KW - Protein Multimerization

KW - Species Specificity

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1084/jem.20121437

DO - 10.1084/jem.20121437

M3 - Article

C2 - 23569328

VL - 210

SP - 933

EP - 949

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

SN - 0022-1007

IS - 5

ER -