Regulatory T cells in autoimmune neuroinflammation

Abstract

Regulatory T cells are the central element for the maintenance of peripheral tolerance. Several subtypes of regulatory T (Treg) cells have been described, and most of them belong to the CD4(+) T-helper (Th) cell lineage. These specific subtypes can be discriminated according to phenotype and function. Forkhead box protein 3 (FoxP3)-expressing natural Treg cells (Tregs) and IL-10-producing, T-regulatory type 1 cells (Tr1) are the best-studied types of CD4(+) regulatory T cells in humans and experimental animal models. It was shown that they play a crucial role during autoimmune neuroinflammation. Both cells types seem to be particularly important for multiple sclerosis (MS). Here, we discuss the role of CD4(+) regulatory T cells in autoimmune neuroinflammation with an emphasis on Tregs and Tr1 cells in MS.

Keywords: FoxP3; Tr1; Treg; autoimmunity; multiple sclerosis; regulatory T cells.

Fig. 1. Impaired function of FoxP3⁺ Tregs in multiple sclerosis

Indicated are the main functional and phenotypic differences between Tregs from healthy donors (healthy) versus Tregs from RRMS patients (multiple sclerosis). Potential deregulated molecules and pathways in RRMS during antigen-presenting cell (APC) and CD4⁺ effector T-cell (Teff) interactions are highlighted. APCs from patients express less CD58, potentially leading to diminished CD58-CD2 costimulation. Thereby inducing lower FoxP3, CD25 and CTLA-4 expression in Tregs of RRMS patients, possibly leading to defects in suppression via IL-2 deprivation, decreased CTLA-4-CD80/86 interaction and reduced IDO induction by APCs. Moreover, a subset of Tregs in patients has lower CD39 expression, possibly resulting in impaired ATP hydrolysis and adenosine generation in concert with Teff CD73. Moreover, higher expression of CD95 and lower levels of CD31, in line with decreased thymic output, indicate changes in subset distribution of Tregs from MS patients. The loss of suppression could lead to an enhanced proinflammatory environment with increased IL-12 and IL-1β secretion by APCs. Increased levels of IL-12 can further induce Tregs to secrete IFN-γ after induction of TBX21. The proinflammatory environment and enhanced CD80/86-CD28 costimulation of Teffs could potentially lead to the induction of pathogenic Th1 and Th17 cells, indicated by TBX21 and RORc transcription and higher expression of CD25.

Fig. 2. Functional changes of Tr1 cells in multiple sclerosis

Indicated are the major functional and phenotypic differences between IL-10-producing Tr1 cells of healthy donors (healthy) versus Tregs from RRMS patients (multiple sclerosis). Possibly involved molecules and pathways in the interaction with antigen-presenting cells (APCs) and CD4⁺ effector T (Teff) cells are highlighted and explained in the text. Tr1 cells are characterized by the co-expression of CD49b and LAG-3. Tr1 cells from healthy donors can secrete large amounts of IL-10, induced for example by IL- 27, CD46, or CD2 costimulation. Tr1 cells also have the potential to secrete granzyme B (GZMB) and express CTLA-4 and are equipped with the molecules CD39/CD73 to hydrolyze ATP and generate suppressive adenosine. The induction of IL-10-secreting Tr1 cells may be impaired in MS patients as result of lower APC CD58 expression, less IL-27 and increased expression of the CD46.2 isoform, associated with proinflammatory responses. If other mechanisms of suppression besides IL-10 secretion are functionally impaired in MS patients is not fully resolved yet. Less IL-10 secretion by Tr1 cells could potentially lead to an increased proinflammatory environment and enhanced Teff induction as indicated in Figure 1 (CD46.1= CD46 isoform Cyt1, CD46.2= CD46 isoform Cyt2).