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Regulation of effector and memory CD8 + T cell differentiation: a focus on orphan nuclear receptor NR4A family, transcription factor, and metabolism

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Abstract

CD8 + T cells undergo rapid expansion followed by contraction and the development of memory cells after their receptors are activated. The development of immunological memory following acute infection is a complex phenomenon that involves several molecular, transcriptional, and metabolic mechanisms. As memory cells confer long-term protection and respond to secondary stimulation with strong effector function, understanding the mechanisms that influence their development is of great importance. Orphan nuclear receptors, NR4As, are immediate early genes that function as transcription factors and bind with the NBRE region of chromatin. Interestingly, the NBRE region of activated CD8 + T cells is highly accessible at the same time the expression of NR4As is induced. This suggests a potential role of NR4As in the early events post T cell activation that determines cell fate decisions. In this review, we will discuss the influence of NR4As on the differentiation of CD8 + T cells during the immune response to acute infection and the development of immunological memory. We will also discuss the signals, transcription factors, and metabolic mechanisms that control cell fate decisions.

Highlights

  • Memory CD8 + T cells are an essential subset that mediates long-term protection after pathogen encounters.

  • Some specific environmental cues, transcriptional factors, and metabolic pathways regulate the differentiation of CD8 + T cells and the development of memory cells.

  • Orphan nuclear receptor NR4As are early genes that act as transcription factors and are highly expressed post-T cell receptor activation.

  • NR4As influence the effector function and differentiation of CD8 + T cells and also control the development of immunological memory following acute infection.

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Abbreviations

NR4As:

Orphan nuclear receptors NR4As

SLEC:

Short-lived effector cells

MPEC:

Memory precursor effector cells

DARs:

Differentially accessible regions

IL:

Interleukin

INF:

Interferon

CD127:

IL-7 receptor alpha subunit

KLRG1:

Killer cell lectin-like receptor G1

TEM:

Effector memory CD8 + T cells

TCM:

Central memory CD8 + T cells

TRM:

Resident memory CD8 + T cells

LCMV:

Lymphocytic choriomeningitis virus

CTLs:

Cytotoxic T-lymphocytes

TCR:

T cell receptor

mTOR:

Mammalian target of rapamycin

FOXO1:

Forkhead box O1

CD122:

IL-2 receptor beta subunit, IL-2Rβ

BLIMP1:

B lymphocyte-induced maturation protein 1

Bcl-6:

B cell lymphoma-6

STAT:

Signal transducer and activator of transcription

ID2:

Inhibitors of DNA binding 2

ID3:

Inhibitors of DNA binding 3

AP-1:

Activator protein-1

bZIP:

Basic leucine zipper proteins

ATF:

Activating transcription factor

BATF:

Basic leucine zipper transcriptional factor ATF-like

MAF:

Musculoaponeurotic fibrosarcoma

IRF:

Interferon regulatory factor

JAK:

Janus kinase

Tyk:

Tyrosine kinase

SH2:

Src homology 2

SOCS:

Suppressors of cytokine signaling

IgE:

Immunoglobulin E

PI3K:

Phosphoinositide 3 kinase

AKT:

Protein kinase B

mTOR:

Mammalian target of rapamycin

AMPK:

5′-Adenosine monophosphate-activated protein kinase

TRAF6:

TNF receptor associated factor 6

FoxP3:

Forkhead box P3

RORγt:

Retinoic acid-related orphan receptor gamma t

GATA3:

GATA binding protein 3

KLF2:

Krüppel-like factor 2

NFAT:

Nuclear factor of activated T cells

GFP:

Green fluorescent protein

scRNAseq:

Single-cell RNA sequencing

ATAC-Seq:

Assay for transposase-accessible chromatin with sequencing

ATP:

Adenosine triphosphate

MHC:

Major histocompatibility complex

HSV:

Herpes simplex virus

NKT:

Natural killer T

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  1. Department of Physiology, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria

    Oladapo O. Oladipo, Bernard O. Adedeji, Samson P. Adedokun, Jibriil A. Gbadamosi & Marzuq Salaudeen

  2. College of Health Sciences, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria

    Oladapo O. Oladipo, Bernard O. Adedeji, Samson P. Adedokun, Jibriil A. Gbadamosi & Marzuq Salaudeen

  3. Department of Biochemistry and Nutrition, Nigerian Institute of Medical Research (NIMR), Yaba, Lagos, Nigeria

    Bernard O. Adedeji

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OOO: conceptualization. OOO, BOA, SPA, JAG, and MS: wrote the manuscript draft. OOO and SPA: review and editing. OOO, BOA, SPA, JAG, and MS: proofreading. All authors agree to the final submission of this manuscript.

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Oladipo, O.O., Adedeji, B.O., Adedokun, S.P. et al. Regulation of effector and memory CD8 + T cell differentiation: a focus on orphan nuclear receptor NR4A family, transcription factor, and metabolism. Immunol Res 71, 314–327 (2023). https://doi.org/10.1007/s12026-022-09353-1

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