T Cells Subsets in the Immunopathology and Treatment of Sjogren's Syndrome

Abstract

Sjogren´s syndrome (SS) is an autoimmune disease whose pathogenesis is characterized by an exacerbated T cell infiltration in exocrine glands, markedly associated to the inflammatory and detrimental features as well as the disease progression. Several helper T cell subsets sequentially converge at different stages of the ailment, becoming involved in specific pathologic roles. Initially, their activated phenotype endows them with high migratory properties and increased pro-inflammatory cytokine secretion in target tissues. Later, the accumulation of immunomodulatory T cells-derived factors, such as IL-17, IFN-γ, or IL-21, preserve the inflammatory environment. These effects favor strong B cell activation, instigating an extrafollicular antibody response in ectopic lymphoid structures mediated by T follicular helper cells (Tfh) and leading to disease progression. Additionally, the memory effector phenotype of CD8+ T cells present in SS patients suggests that the presence of auto-antigen restricted CD8+ T cells might trigger time-dependent and specific immune responses. Regarding the protective roles of traditional regulatory T cells (Treg), uncertain evidence shows decrease or invariable numbers of circulating and infiltrating cells. Nevertheless, an emerging Treg subset named follicular regulatory T cells (Tfr) seems to play a critical protective role owing to their deficiency that enhances SS development. In this review, the authors summarize the current knowledge of T cells subsets contribution to the SS immunopathology, focusing on the cellular and biomolecular properties allowing them to infiltrate and to harm target tissues, and that simultaneously make them key therapeutic targets for SS treatment.

Keywords: Sjogren’s syndrome; T cell subsets; emerging T cells; immunomodulatory cytokines; infiltrating T cells; therapeutic targets.

Figure 1

Sequential roles of T cells in SS progression: flares of main implications. Tolerance loss drives T cell activation and migration to exocrine glands, where they provide several factor that make the auspicious environment for the pathology establishment: Th1 and Th17 cells contribute for inflammatory and detrimental environment by secreting cytokines like IFN-γ, TNF-α and IL-17, triggering sustained T cells migration and hyperactivation. Th2 cells are suggested to modulate early B cells response, and to contribute with Th17 cells in initial ESL development, allowing Tfh cells to establish and to provide the necessary factors to trigger B cells response; thus, leading to progressive tissue damage. Treg cells dysfunctionality and low frequency are suggested to contribute to periphery loss tolerance. Positive T and B cells feedback trough intercellular contact and soluble factor allow a sustained B cells response and the onset of clinical features. GC, Germinal Center; ELS, Ectopic Lymphoid Structures.

Figure 2

Schematic representation of the several potential T cells alternative targets for SS therapeutic. Novel biomolecules are arising as key factor for controlling several aspects of T cells immunobiology, encompassing those directed towards their activation and migratory sate, as well as those implicated in modulating their inflammatory phenotype.