T cells in Systemic Lupus Erythematosus

doi:10.1016/j.coi.2016.09.001

Current Opinion in Immunology

Volume 43, December 2016, Pages 32-38

https://doi.org/10.1016/j.coi.2016.09.001 Get rights and content

Highlights

•
T cell transcriptomes can stratify patients.
•
T_H17, Double-Negative and γδT cells contribute to lupus nephritis.
•
T cell support autoantibody production in lymphoid and non-lymphoid organs in SLE.
•
Aberrant activation of several pathways drives T cell malfunction in SLE.
•
CaMKIV, ROCK, STAT3 AND PI3K/AKT/mTOR represent therapeutic targets.

Systemic Lupus Erythematosus is an autoimmune disorder caused by a complex combination of genetic, epigenetic and environmental factors. Different polymorphisms and epigenetic modifications lead to altered gene expression and function of several molecules which lead to abnormal T cell responses. Metabolic and functional alterations result in peripheral tolerance failures and biased differentiation of T cells into pro-inflammatory and B cell-helper phenotypes as well as the accumulation of disease-promoting memory T cells. Understanding these T cell alterations and their origins is necessary to develop more accurate patient classification systems and to discover new therapeutic targets.

Graphical abstract

Introduction

SLE is a complex autoimmune disease characterized by defects in cellular apoptotic debris clearance, an interferon (IFN) expression signature in peripheral lymphocytes, and the breakdown of peripheral tolerance mechanisms resulting in the generation of autoantibodies and damage of tissues and organs, including the kidney (reviewed in [1]). T cells play a major role in SLE pathogenesis, amplifying inflammation by secretion of pro-inflammatory cytokines, helping B cells to generate autoantibodies, and maintaining the disease through the accumulation of autoreactive memory T cells. Many aberrations in T cell expression and function have been described as related to abnormal T cell activation in SLE patients (reviewed in [2]) which leads to reduced TCR activation threshold and reduced peripheral tolerance.

During the last few years, special interest has been focused on the role of T cell subsets in SLE pathology, the molecular pathways involved in their aberrant differentiation and their varied metabolic needs. In this review we discuss the role of T cells in SLE as well as current knowledge of associated molecular alterations. Clearer understanding of these aberrations will lead to the development of new and more specific SLE treatments.

Section snippets

SLE T cells show widespread inflammatory gene expression

In addition to the IFN gene signature, T cell transcriptome data highlights induction of pathways related to mitochondria, glycolysis and nucleotide metabolism, as well as genes induced in patients with anti-dsDNA antibodies and nephritis. T cell gene expression can also be used to stratify patients into subtypes which may facilitate precision medicine approaches [3^•]. Many of the induced genes are present in other peripheral blood cells [4^•]. While some of the altered genes and pathways are

T cells, a complex group of different cells with specific functions that are altered in SLE

Recent advances in detection methods reveal immense complexity in peripheral blood T cell subpopulations [6], including different effector, memory and regulatory subtypes.

While the immune system relies on complex interactions of different cells, these can be broadly classified as pro-inflammatory or anti-inflammatory. T cells can drive immunosuppression or inflammation and antibody production, based on the proportion of different T cell subpopulations and their signaling function. The

Reduced cytotoxicity in SLE CD8T cells

CD8T cells control infection, malignancy and autoreactive immunity by release of cytotoxic proteins such as perforin and granzymes. CD8T cells in SLE have dampened cytotoxic function that can lead to increased risk of infection, which may also trigger autoimmunity [7]. Two recent studies showed defective CD8 responses to viral antigens, and proposed either a reduction in effector memory CD8T cells positive for signaling lymphocytic activation molecule family member 4 (SLAMF4) which is related

Double-Negative T cells in SLE: from suppressive to pro-inflammatory

Double-Negative (DN) T cells, defined as TCRαβ⁺CD4⁻CD8⁻, can result from inactivation or exhaustion of autoreactive, or continuously stimulated CD8T cells, such as are found in chronic infection [12, 13]. Under normal conditions an immunosuppressive role has been attributed to these cells, both in mouse and human, through antigen-competition and T cell killing by Fas-FasL or perforin and granzyme secretion [14, 15]. However, in SLE patients these cells are related to pathogenesis and kidney

CD4T helper cells, supporting inflammation and autoantibody production in SLE

CD4+ helper T cells make major contributions to antibody production and tissue inflammation, and are readily linked to development of SLE and Lupus nephritis. Aberrant expression of different molecules and signaling leads to increased TCR stimulation and circumvention of peripheral tolerance mechanisms (Figure 2 and [2]). In addition, increased accumulation of effector/memory T cells has been described in these patients, which is thought to result from activation of PI3K/AKT/mTOR transduction,

Increased numbers of T helper 17 cells promote kidney disease and autoantibody production

T_H17 cells and the cytokine IL-17 are related to SLE disease and especially with lupus nephritis (Figure 1). IL-17 is a potent pro-inflammatory cytokine, the levels of which correlate with the development of lupus-like nephritis in several mouse models. In addition, the proportion of T_H17 cells and the amount of IL-17 in serum are increased in SLE patients, especially in those with kidney disease (Figure 1 and reviewed in [27]).

There are several molecular aberrations in SLE patients that lead

Extrafollicular T cells help B cells to produce autoantibodies in SLE

SLE is characterized by production of high affinity autoantibodies against nuclear antigens, of which anti-dsDNA has been most correlated with disease activity [1]. The IgG isotype and somatic hypermutation in these autoantibodies indicates that that B cells are activated in a T-cell dependent-manner [38]. B cell activation depends on interaction with T follicular helper (T_FH) cells, a subtype of CD4T cells positive for CXCR5, PD-1, ICOS and CD40L. In addition these cells express high levels of

γδT T cells

γδT are a minor population of T cells related to SLE pathology, both in humans and in mouse models, through their antigen-presenting function, pro-inflammatory cytokine secretion, interaction with T_reg, and their promotion of antibody production by providing B cell help even in absence of antigen (reviewed in [49]).

Recently, a report showed that one subtype of the γδT cell population, Vδ2, is reduced in peripheral blood but accumulates in kidneys from SLE patients. These cells display an

Impaired regulatory T cells in SLE

T regulatory cells (T_reg) include several subsets of T cells playing a critical role in the control of the immune system. While the classical T_reg are a subset of the TCRαβ CD4⁺ cells, TCRαβ CD8⁺ and γδT cells have also been described to have regulatory activity (reviewed in [51]). While it is well accepted that there is a dysregulation in immune response control by T_reg in SLE patients, the cause remains unclear.

Conclusions

T cells play an important role driving and maintaining SLE disease. Decreased cytotoxicity of CD8T cells has a role in increased risk of infection. Up-regulation and accumulation of T follicular helper, γδT cells, T_H17 and DN T cells, and down-regulation of suppressive function of the different regulatory subsets, drive and maintain the synthesis of autoantibodies and have a strong influence over kidney pathology in SLE patients (Figure 1). At the molecular level, the pathways and molecular

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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T cells in Systemic Lupus Erythematosus

Highlights

Graphical abstract

Introduction

Section snippets

SLE T cells show widespread inflammatory gene expression

T cells, a complex group of different cells with specific functions that are altered in SLE

Reduced cytotoxicity in SLE CD8T cells

Double-Negative T cells in SLE: from suppressive to pro-inflammatory

CD4T helper cells, supporting inflammation and autoantibody production in SLE

Increased numbers of T helper 17 cells promote kidney disease and autoantibody production

Extrafollicular T cells help B cells to produce autoantibodies in SLE

γδT T cells

Impaired regulatory T cells in SLE

Conclusions

References and recommended reading

Sci Transl Med

Arthritis Rheum

PLoS Pathog

J Immunol Baltim Md 1950

Cell Immunol

J Biol Chem

J Biol Chem

Arthritis Rheum

J Immunol Baltim Md 1950

Eur J Immunol

J Immunol Res

J Immunol Baltim Md 1950

Ann Rheum Dis

Systemic lupus erythematosus

N Engl J Med

T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity

J Clin Invest

T cell transcriptomes describe patient subtypes in systemic lupus erythematosus

PLOS ONE

Personalized immunomonitoring uncovers molecular networks that stratify Lupus patients

Cell

Mapping the diversity of follicular helper t cells in human blood and tonsils using high-dimensional mass cytometry analysis

Cell Rep

Promotion and prevention of autoimmune disease by CD8+ T cells

J Autoimmun

T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection

Nature

Programmed cell death 1 and Helios distinguish TCR-αβ+ double-negative (CD4−CD8−) T cells that derive from self-reactive CD8 T cells

J Immunol Baltim Md 1950

Double-Negative regulatory T cells: non-conventional regulators

Immunol Res

Pro-inflammatory self-reactive T cells are found within murine TCR-αβ(+) CD4(−) CD8(−) PD-1(+) cells

Eur J Immunol

Characterization of the immunoregulatory function of human TCR-αβ+ CD4-CD8- double-negative T cells

Eur J Immunol

TCR/self-antigen interactions drive double-negative T cell peripheral expansion and differentiation into suppressor cells

J Immunol Baltim Md 1950

Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys

J Immunol Baltim Md 1950

Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus

J Immunol Baltim Md 1950

cAMP-responsive element modulator α (CREMα) trans-represses the transmembrane glycoprotein CD8 and contributes to the generation of CD3+CD4-CD8- T cells in health and disease

J Biol Chem

CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance

J Clin Invest

IL-7 abrogates the immunosuppressive function of human double-negative t cells by activating Akt/mTOR signaling

J Immunol Baltim Md 1950

Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: correlation with disease activity

Cytokine

Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10+ B cells in patients with new-onset systemic lupus erythematosus

J Rheumatol

Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity

Arthritis Rheumatol (Hoboken, NJ)