T Cells in the Pathogenesis of Sjögren’s Syndrome: More Than Just Th1 and Th2

1

Introduction

In the last few decades, T lymphocytes have been widely investigated in the pathogenic scenario of autoimmune diseases. To date, a consistent body of evidence points out the key role of this arm of the immune system in the induction and perpetuation of primary Sjögren’s syndrome (SS). The first milestone in this field is the study by Fox et al. who reported in 1983 that the vast majority of infiltrating cells in minor salivary glands (MSGs) of SS patients were T lymphocytes. In fact, these lymphocytes were activated CD4+ cells polarized toward a T helper (Th) 1 phenotype. On this basis, and according to the so-called “Th1/Th2 paradigm,” which emerged in the 1990s, SS was classified as a Th1-driven autoimmune disease. In recent years, however, this paradigm was challenged by the discovery of an increasing number of different T-lymphocyte subsets. Therefore several studies attempted to characterize the involvement of regulatory T (Treg) cells, Th17, and other T-cell subpopulations in the induction and perpetuation of chronic autoimmune sialadenitis ( Fig 13.1 ).

Herein we summarize the recent insights on the T-lymphocyte pathogenic role in SS.

2

Regulatory T Cells in Sjögren’s Syndrome

Treg cells represent a specialized T-lymphocyte subset able to orchestrate physiological immune responses against pathogens and to interfere with aberrant immune responses against self-antigens, thereby preventing autoimmunity. In 1995, the group of Sakaguchi and colleagues identified a CD4+ T-cell population expressing high surface levels of the interleukin (IL) 2 receptor α-chains (CD25) that was able to prevent systemic autoimmunity in thymectomized mice. Subsequent studies in humans revealed that these cells, named regulatory because of their capability to “regulate” autoreactive immune responses, were consistently present in the peripheral blood (PB) of healthy subjects. In the light of the most recent studies, CD4+ Treg cells can be divided into: (1) thymus-derived Treg cells that develop in the thymus in early phases of life and whose phenotype and function remain stable overtime; (2) peripherally derived Treg cells, including Tr1 and Th3, that arise from the extrathymic conversion of effector T cells in the presence of a specific cytokine microenvironment and that are highly flexible and prompt to expand under appropriate signals. Although a variety of molecules have been identified in addition to CD25 on Treg cell surface, the forkhead box protein P3 (FoxP3) transcriptional factor remains to date the most specific Treg marker that is also required to confer a regulatory function. The upregulation of FoxP3 in naive T cells, namely the polarization toward a Treg phenotype, is mainly driven by transforming growth factor (TGF)-β.

The capability of Treg cells to hamper autoimmune responses by selective deletion of autoreactive lymphocytes via either cell–cell contact or the release of soluble mediators, including IL-10 and TGF-β, represented the rationale to investigate their possible numerical or functional abnormalities in systemic and organ-specific autoimmune disorders. A consistent number of studies have been performed in the last 10 years in SS, often yielding conflicting results. Indeed, it should be taken into account that recent studies put forward the hypothesis that high surface expression of CD25 is not mandatory to identify Treg cells, because FoxP3+ suppressive T lymphocytes lacking CD25 have been identified in the PB of normal subjects and patients with systemic lupus erythematosus or SS.

On this basis, although the aforementioned studies provided conflicting results concerning the proportion of circulating Treg cells in the PB of SS patients, there is general agreement regarding the consistent expression of FoxP3, independently of that of CD25, within the mononuclear cell infiltrate of SS-MSGs. Of interest, some authors identified a direct association between FoxP3 glandular expression and the severity of the local inflammatory infiltrate. This observation is similar to that reported in rheumatoid synovial tissue and allows the speculation that Treg cells are actually present in the inflammatory infiltrate, but their suppressive activity may be affected by the local microenvironment. This hypothesis is further supported by in vitro studies revealing that SS circulating Treg cells display a normal suppressive function.

In conclusion, although it is difficult to verify the function of Treg cells in vivo and therefore to draw definitive conclusions, it is reasonable to postulate their involvement in disease pathogenesis ( Table 13.1 ).