T cells and autoimmune kidney disease

Key Points

  • Autoantibodies directed against or crossreacting with kidney antigens form immune complexes in the periphery or in situ and activate complement; immune complexes deposited in the kidney can alter the structure and function of resident kidney cells and facilitate immune-cell infiltration

  • Various T-cell subtypes exist: T regulatory cells prevent autoimmunity, whereas T follicular helper (TFH) cells, T-helper (TH) type 1 and type 2 cells, CD8+ T cells and resident memory T cells are implicated in the pathogenesis of autoimmune nephropathies

  • IL-17-producing T cells (γδT cells, TH17 cells and double-negative T cells) promote renal impairment by supporting self-reactive B-cell survival, differentiation, and subsequent antibody production, and by promoting inflammation in infiltrated tissues

  • Autoimmune kidney disease is also influenced by molecular aberrations in T cells; for example, increased expression of the transcription factors CREM and STAT3 drives differentiation of TH17 and TFH cells

  • Alteration in molecules such as CaMKIV, ROCK and mTOR also influence the inflammatory response and contribute to kidney cell damage in autoimmune disease

  • Some of these molecules control the function of glomerular epithelial cells and their inhibition has been shown to have therapeutic value in preclinical studies; they might therefore represent suitable targets for clinical trials

Abstract

Glomerulonephritis is traditionally considered to result from the invasion of the kidney by autoantibodies and immune complexes from the circulation or following their formation in situ, and by cells of the innate and the adaptive immune system. The inflammatory response leads to the proliferation and dysfunction of cells of the glomerulus, and invasion of the interstitial space with immune cells, resulting in tubular cell malfunction and fibrosis. T cells are critical drivers of autoimmunity and related organ damage, by supporting B-cell differentiation and antibody production or by directly promoting inflammation and cytotoxicity against kidney resident cells. T cells might become activated by autoantigens in the periphery and become polarized to secrete inflammatory cytokines before entering the kidney where they have the opportunity to expand owing to the presence of costimulatory molecules and activating cytokines. Alternatively, naive T cells could enter the kidney where they become activated after encountering autoantigen and expand locally. As not all individuals with a peripheral autoimmune response to kidney antigens develop glomerulonephritis, the contribution of local kidney factors expressed or produced by kidney cells is probably of crucial importance. Improved understanding of the biochemistry and molecular biology of T cells in patients with glomerulonephritis offers unique opportunities for the recognition of treatment targets for autoimmune kidney disease.

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Figure 1: Sequence of events in the development of autoimmune nephritis.
Figure 2: Molecular pathways involved in the regulation of T-cell differentiation and cytokine production.
Figure 3: Differentiation and functional control of T-cell subsets.

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Acknowledgements

S.J.B. is supported by a T32 training grant from NIAID, NIH to G.C.T. The work of D.K. is funded by French state funds within the Investissements d'Avenir programme (ANR-11-IDEX-0004-02; LabEx Transimmunom); the European Research Council Advanced Grant (ERC-2012-AdG, TRiPoD, Agreement number 322856); the Assistance Publique – Hopitaux de Paris, France; the Sorbonne University, Pierre and Marie Curie Medical School, Paris, France; and the Institut National de la Santé et de la Recherche Médicale (INSERM). The work of G.C.T. is supported by grants from the NIH.

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All authors contributed equally to researching data for the article, discussion of the content, and revising or editing the manuscript before submission.

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PowerPoint slides

Glossary

γδT cells

T-cell subtype characterized by the expression of a unique T-cell receptor composed of one γ and one δ chain. Although their prevalence is small compared to that of αβT cells, they are frequently present in tissues at high risk of infection and are involved in the initiation and propagation of immune responses in physiological and pathological conditions.

NETosis

A specific process of cell death mediated by neutrophils, which generate neutrophil extracellular traps (NETs).

T-helper (TH) type 1 cells

Subtype of CD4+ αβT cell characterized by the secretion of IFNγ, IL-2 and TNFβ. Their principal transcription factor, T-bet, is expressed following activation of STAT-1 through the IL-12 receptor.

NKT cells

(Natural killer T cells). An innate-like lymphocyte population expressing markers associated with T cells and NK cells, with an important role in immune regulation through the production of cytokines.

Plasma cells

Long-lived effector B cells responsible for humoral memory.

T follicular helper (TFH) cells

Subtype of CD4+ T cells that express BCL6 and support B-cell activation and differentiation in germinal centres.

Plasmablasts

Short-lived effector B cells that rapidly produce antibodies upon activation. They can differentiate into plasma cells.

Peripheral T-cell tolerance

Combination of mechanisms that control autoreactive T-cell responses in the periphery. These mechanisms can be either cell-intrinsic (anergy and activation-induced cell death) or extrinsically mediated by T regulatory cells.

Vδ2 T cells

Proinflammatory subtype of γδT cells, which are activated through phospho-antigens.

Double-negative (DN) T cells

A subtype of TCRαβ T cells, which differentiate from autoreactive CD8+ T cells. They are found at increased levels in several autoimmune and chronic inflammatory diseases. In lupus nephritis kidneys they have been found to produce IL-17.

αβT cells

Subtype of T cells that express a T-cell receptor composed of an α and a β chain. They express the co-receptors CD4 or CD8.

Ectopic lymphoid follicles

Discrete structures in which B cells and T cells interact in non-lymphoid tissues. The follicles are formed during autoimmunity or chronic inflammation as a consequence of immune cell infiltration.

Immunoglobulin class-switching

Biological mechanism whereby activated B cells change the isotype of antibodies that they produce. This process is also known as class-switch recombination.

TH2 cells

Subtype of CD4+ αβT cell characterized by the secretion of IL-4, IL-5, IL-6, IL-9, IL-13, and IL-17E (IL-25), which support the humoral response. GATA-3 is their principal transcripton factor, which is expressed following activation of STAT-6 by IL-4.

Tissue-resident memory T cells

T cells, which after tissue infiltration, activate an mTOR-dependent mechanism that leads to a change in phenotype to resident memory T cells. They can have either a protective or harmful role in physiology and pathology.

Central memory T cells

Long-term surviving memory T cells characterized by the expression of L-selectin and CCR7 and the secretion of several cytokines. They present self-renewal capacity and localize in lymph nodes.

T cell clonotypes

T cells that share the same T-cell receptor.

Activation-induced cell death

Mechanism of progammed cell death mediated by the interaction of Fas and FasL in restimulated T cells. It represents one of the peripheral tolerance mechanisms for T cells.

CD3 complex

CD3 is a complex of molecules associated with and used by the T-cell receptor to instigate T-cell signalling. It comprizes six molecules: an δ-chain, a γ-chain, two ε chains and two ζ chains.

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Suárez-Fueyo, A., Bradley, S., Klatzmann, D. et al. T cells and autoimmune kidney disease. Nat Rev Nephrol 13, 329–343 (2017). https://doi.org/10.1038/nrneph.2017.34

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