The pathology of T cells in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies. Thus, the condition was traditionally classified as a "B-cell disease". Compelling evidence has however shown that without the assistance of the helper T lymphocytes, it is indeed difficult for the "helpless" B cells to become functional enough to trigger SLE-related inflammation. T cells have been recognized to be crucial in the pathogenicity of SLE through their capabilities to communicate with and offer enormous help to B cells for driving autoantibody production. Recently, a number of phenotypic and functional alterations which increase the propensity to trigger lupus-related inflammation have been identified in lupus T cells. Here, potential mechanisms involving alterations in T-cell receptor expressions, postreceptor downstream signalling, epigenetics, and oxidative stress which favour activation of lupus T cells will be discussed. Additionally, how regulatory CD4+, CD8+, and γδ T cells tune down lupus-related inflammation will be highlighted. Lastly, while currently available outcomes of clinical trials evaluating therapeutic agents which manipulate the T cells such as calcineurin inhibitors indicate that they are at least as efficacious and safe as conventional immunosuppressants in treating lupus glomerulonephritis, larger clinical trials are undoubtedly required to validate these as-yet favourable findings.

Figure 1

Development of lupus T cells, their interactions with T-regulatory cells and B cells, and alterations of the intracellular physiology of effector lupus T cells. Naïve T cells develop into follicular T-helper cells which cross-talk with B cells for autoantibody production under the stimulation of IL6, IL-21, and ICOS. Naïve T cells develop into effector CD4+ and Th17+ T cells which produce proinflammatory cytokines and exhibit altered intracellular physiology including clustering of CD3-TCR, oxidative-stress induced calcium flux, and consequent change in mRNA transcriptions of various important genes (see text for details). Abbreviations: Tregs, regulatory T cells; ICOS, inducible T-cell costimulator; F-Th, follicular T-helper cells; Syk, spleen tyrosine kinase; CaMKIV, calcium/calmodulin-dependent kinase IV; CREB/CREM, cAMP response element (CRE) binding protein (CREB)/CRE-modulator (CREM); NF-ATc2, nuclear factor of activated T cells; Elf-1, transcription factor Elf-1; Ca²⁺, calcium ion; PP2A, protein phosphatase 2A; mTOR, mitochondrial transmembrane potential and mammalian target of rapamycin; +P, phosphorylation; −P, dephosphorylation.