Faculty Opinions recommendation of CD4(+) T cell effectors can become memory cells with high efficiency and without further division.

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester–based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA− CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA− CCR7− effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-γ. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-γ. Longitudinal analysis of HIV epitope–specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-γ–producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2–producing CD4+ T cells and that IFN-γ only–producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-γ only–producing cells that lack self-renewal capacity.

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Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation

Journal of Experimental Medicine ◽

10.1084/jem.20050227 ◽

2005 ◽

Vol 202 (5) ◽

pp. 697-706 ◽

Cited By ~ 185

Author(s):

Dawn M. Jelley-Gibbs ◽

Deborah M. Brown ◽

John P. Dibble ◽

Laura Haynes ◽

Sheri M. Eaton ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

High Efficiency ◽

Influenza Infection ◽

Cd4 T Cell ◽

Intermediate Phenotypes ◽

Donor T Cells ◽

T Cell Transfer ◽

Kinetics Of

The kinetics of presentation of influenza virus–derived antigens (Ags), resulting in CD4 T cell effector and memory generation, remains undefined. Naive influenza-specific CD4 T cells were transferred into mice at various times after influenza infection to determine the duration and impact of virus-derived Ag presentation. Ag-specific T cell responses were generated even when the donor T cells were transferred 3–4 wk after viral clearance. Transfer of naive CD4 T cells during early phases of infection resulted in a robust expansion of highly differentiated effectors, which then contracted to a small number of memory T cells. Importantly, T cell transfer during later phases of infection resulted in a modest expansion of effectors with intermediate phenotypes, which were capable of persisting as memory with high efficiency. Thus, distinct stages of pathogen-derived Ag presentation may provide a mechanism by which T cell heterogeneity is generated and diverse memory subsets are maintained.

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Rapid default transition of CD4 T cell effectors to functional memory cells

Journal of Experimental Medicine ◽

10.1084/jem.20070041 ◽

2007 ◽

Vol 204 (9) ◽

pp. 2199-2211 ◽

Cited By ~ 73

Author(s):

K. Kai McKinstry ◽

Susanne Golech ◽

Won-Ha Lee ◽

Gail Huston ◽

Nan-Ping Weng ◽

...

Keyword(s):

Gene Expression ◽

T Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cd4 T Cell ◽

Effector Memory ◽

Memory Cells ◽

Two Stages

The majority of highly activated CD4 T cell effectors die after antigen clearance, but a small number revert to a resting state, becoming memory cells with unique functional attributes. It is currently unclear when after antigen clearance effectors return to rest and acquire important memory properties. We follow well-defined cohorts of CD4 T cells through the effector-to-memory transition by analyzing phenotype, important functional properties, and gene expression profiles. We find that the transition from effector to memory is rapid in that effectors rested for only 3 d closely resemble canonical memory cells rested for 60 d or longer in the absence of antigen. This is true for both Th1 and Th2 lineages, and occurs whether CD4 T cell effectors rest in vivo or in vitro, suggesting a default pathway. We find that the effector–memory transition at the level of gene expression occurs in two stages: a rapid loss of expression of a myriad of effector-associated genes, and a more gradual gain of expression of a cohort of genes uniquely associated with memory cells rested for extended periods.

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CD4 T–cell memory can persist in the absence of class II

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2000.0581 ◽

2000 ◽

Vol 355 (1395) ◽

pp. 407-411 ◽

Cited By ~ 24

Author(s):

Susan L. Swain

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Specific Antigen ◽

Class Ii ◽

Cd4 T Cell ◽

T Cell Memory ◽

Memory Cells ◽

Short Period ◽

Memory Cd4 T Cells

To understand how memory CD4 T cells are generated we have re–examined the requirements for continuing antigen stimulation in the generation and persistence of this population. We find that specific antigen is only required for a short period during the activation of naive CD4 Tcells and is not required for memory generation from activated CD4 T cells or for persistence of resting memory cells generated by transfer of activated CD4 to adoptive hosts. Moreover, transfer of activated CD4 T cells to class–II–deficient hosts, indicates that T cR–class II major histocompatibility interaction is also unnecessary for either the transition from activated CD4 T cell to resting memory cells or for persistence over an eightweek period. Thus the signals regulating generation and maintenance of memory are fundamentally different from those which regulate the expansion of effector CD4 T–cell populations which include antigen itself and the CD4 T–cell autocrine cytokines induced by antigen.

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Memory CD4+ T cell subsets in tumor draining lymph nodes of breast cancer patients: A focus on T stem cell memory cells

Cellular Oncology ◽

10.1007/s13402-017-0352-6 ◽

2017 ◽

Vol 41 (1) ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Yasmin Vahidi ◽

Zahra Faghih ◽

Abdol-Rasoul Talei ◽

Mehrnoosh Doroudchi ◽

Abbas Ghaderi

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

T Cell ◽

Lymph Nodes ◽

Cancer Patients ◽

T Cell Subsets ◽

Cd4 T Cell ◽

Memory Cells ◽

Breast Cancer Patients ◽

Draining Lymph Nodes

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CD2-mediated stimulation of the naive CD4+ T-cell subset promotes the development of skin-associated cutaneous lymphocyte antigen-positive memory cells

Immunology ◽

10.1111/j.1365-2567.1996.tb00006.x ◽

1996 ◽

Vol 88 (2) ◽

pp. 207-213 ◽

Cited By ~ 7

Author(s):

L. LIU ◽

A. FOER ◽

J. SESTERHENN ◽

U. REINHOLD

Keyword(s):

T Cell ◽

Cell Subset ◽

Cd4 T Cell ◽

Memory Cells ◽

Lymphocyte Antigen ◽

T Cell Subset ◽

Cutaneous Lymphocyte Antigen ◽

Stimulation Of

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The Tumor Antigen Cyclin B1 Hosts Multiple CD4 T Cell Epitopes Differently Recognized by Pre-Existing Naive and Memory Cells in Both Healthy and Cancer Donors

The Journal of Immunology ◽

10.4049/jimmunol.1402548 ◽

2015 ◽

Vol 195 (4) ◽

pp. 1891-1901 ◽

Cited By ~ 9

Author(s):

Claire Chevaleyre ◽

Nadine Benhamouda ◽

Emmanuel Favry ◽

Elizabeth Fabre ◽

Anais Mhoumadi ◽

...

Keyword(s):

T Cell ◽

Tumor Antigen ◽

Cyclin B1 ◽

Cd4 T Cell ◽

Memory Cells ◽

T Cell Epitopes

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Genomic profiling of T cell activation reveals dependency of memory T cells on CD28 costimulation

10.1101/421099 ◽

2018 ◽

Cited By ~ 3

Author(s):

Dafni A. Glinos ◽

Blagoje Soskic ◽

Luke Jostins ◽

David M. Sansom ◽

Gosia Trynka

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Memory T Cells ◽

Cd4 T Cell ◽

Genomic Profiling ◽

Memory Cells ◽

Cell Responses

SummaryT cell activation is a critical driver of immune response and if uncontrolled, it can result in failure to respond to infection or in excessive inflammation and autoimmunity. CD28 costimulatory pathway is an essential regulator of CD4 T cell responses. To deconvolute how T cell receptor (TCR) and CD28 orchestrate activation of human CD4 T cells we stimulated cells using varying intensities of TCR and CD28 signals followed by gene expression profiling. We demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Strikingly, cell cycle and cell division are sensitive to CD28 in memory cells, but under TCR control in naive cells, in contrast to the paradigm that memory cells are CD28-independent. Using a combination of chromatin accessibility and enhancer profiling, we observe that IRFs and Blimp-1 (PRDM1) motifs are enriched in naive and memory T cells in response to TCR. In contrast, memory cells initiate AP1 transcriptional regulation only when both TCR and CD28 are engaged, implicating CD28 as an amplifier of transcriptional programmes in memory cells. Lastly, we show that CD28-sensitive genes are enriched in autoimmune disease loci, pointing towards the role of memory cells and the regulation of T cell activation through CD28 in autoimmune disease development. This study provides important insights into the differential role of CD28 in naive and memory T cell responses and offers a new platform for design and interpretation of costimulatory based therapies.One-sentence summaryGenomic profiling of CD4 T cell activation reveals a sensitivity switch from TCR in naive to CD28 in memory cells.

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