Targeting Inflammatory T Cells in Multiple Sclerosis: Current Therapies and Future Challenges ws

Review Article

Austin J Mult Scler & Neuroimmunol. 2015;2(1): 1009.

Targeting Inflammatory T Cells in Multiple Sclerosis: Current Therapies and Future Challenges

Loretta Tuosto*

Istituto Pasteur-Fondazione Cenci Bolognetti,Department of Biology and Biotechnology “Charles Darwin”, Sapienza University, Rome, Italy

*Corresponding author: Loretta Tuosto, Department of Biology and Biotechnology “Charles Darwin”, Sapienza University, 00185-Rome, Italy

Received: September 15, 2014; Accepted: February 18, 2015; Published: February 20, 2015


Multiple Sclerosis (MS) is an autoimmune inflammatory disorder of the Central Nervous System (CNS), affecting more than one million people worldwide. The pathogenesis of MS involves several genetic and environmental factors, which ultimately lead to the activation of autoreactive T cells in the periphery, their migration into the CNS, where they trigger an acute inflammatory response, thus mediating primary demyelination and axonal damage. Most information on MS derives from studies in animal models of experimental autoimmune encephalomyelitis (EAE), which exhibit many similarities to the pathology of MS. Two distinct subsets of autoreactive T cells have been primarily involved in the pathogenesis of both EAE and MS: the interferon (IFN)-γ producing CD4+ T helper (Th) 1 and interleukin (IL)-17 producing Th17 cells. The activity of these cells is controlled by specific regulatory T cells (Treg), which by secreting antiinflammatory cytokines such as IL-4, IL-10 and tumour growth factor (TGF)-β efficiently inhibit Th1 and Th17 cells.

In this review, we summarize current knowledge on the role and function of pro-inflammatory and Treg subsets in MS. We also discuss the action of current and novel therapies aimed to dampen inflammatory T cells.

Keywords: Multiple sclerosis; Inflammatory T cells; Regulatory T cells;Therapy; Costimulation


MS: Multiple Sclerosis; CNS: Central Nervous System; EAE: Experimental Autoimmune Encephalomyelitis; IFN: Interferon; Th: T helper; IL: Interleukin; TGF: Tumour Growth Factor; RR: Relapseremitting; SP: Secondary Progressive; PP: Primary Progressive; BBB: Blood-Brain Barrier; APC: Antigen Presenting Cell; DC: Dendritic Cell; MBP: Myelin Basic Protein; PLP: Proteolipid Protein; MOG: Myelin Oligodendrocyte Glycoprotein; Tregs: Regulatory T Cells; GA: Glatiramer Acetate; GITRL: Glucocorticoid-induced TNF Receptor Ligand; ASEs: Adverse Side-Effects; NK: Natural Killer; TCR: T Cell Receptor; PI3K: Phosphatidylinositol-3 Kinase; PIP2: Phosphatidylinositol 3,4-biphosphate; PIP3: Phosphatidylinositol 3,4,5-triphosphate; Ab: Antibody; GITR: Glucocorticoid-Induced TNF Receptor-related Protein


MS is an autoimmune chronic inflammatory disorder characterized by demyelination and remyelination events and by the loss of sensory and motor functions. Two third of MS patients present the relapsing-remitting (RR) course, which is characterized by relapses usually followed by periods of recovery or remission, but one third of patients progresses to chronic secondary progressive (SP) disease [1,2]. A minority of patients (10-20%) experiences a primary progressive disease (PP), which is characterized by a gradual and constant decline in their neurological functions from the onset of disease [3]. Inflammation is present at all stages of MS [4] and pro-inflammatory cytokines/chemokines play a critical role in the pathophysiology of MS by compromising the blood- brain barrier (BBB) integrity, recruiting immune cells from the periphery, and activating resident microglia. Conversion of MS from RR to progressive phases has been related to prolonged chronic inflammation in the CNS. Moreover, both SPMS and PPMS patients have generalized inflammation in the whole brain accompanied by cortical demyelination and diffuse white matter injury [4].

Although several cell types within the CNS may contribute to the production of pro-inflammatory cytokines and chemokines, activated autoreactive T cells have a key role in inflammatory demyelination [5]. Indeed, the cytokine and chemokine-producing phenotype of self-reactive T cells in MS patients determines the ability of these cells to cross BBB and cause inflammation in the CNS, thus contributing to disease progression.

This article reviews the current knowledge on the contribution of different T cell subsets in the pathogenesis of MS and discusses the current and novel therapeutic strategies, which aim to dampen the pathogenic inflammatory T-cell response.

Inflammatory T helper cell subsets in MS: Th1 and Th17 cells

The more accepted pathogenic model for both EAE and MS is that autoreactive myelin-specific CD4+ T cells are activated in the periphery, entered the CNS by crossing the BBB and are reactivated by resident antigen-presenting cells (APC), mainly of which is microglial cells [5,6]. The priming and activation of autoreactive myelin-specific CD4+ T cells likely occurs in peripheral lymph nodes, where the dendritic cells (DC) may present myelin epitopes to naive T cells, thus inducing the activation and differentiation of autoreactive effector/memory T helper cells, which in turn migrate to the CNS and cause tissue damage and demyelination. Several evidences support a function for myelin proteins, such as MBP (myelin basic protein), PLP (proteolipid protein) and MOG (myelin oligodendrocyte glycoprotein), as relevant antigens in both EAE and MS [7-11]. In EAE, myelin-specific T cell responses seem to initiate in the CNSdraining cervical lymph nodes, thus suggesting that myelin proteins are constitutively presents in some lymph nodes [12]. Moreover, high avidity myelin-specific CD4+ T cells have been isolated from the periphery of MS patients [13,14].

It has been thought for a long time that the pathogenetic cells mediating MS were CD4+ Th1 cells, producing large quantity of IFN-γ driven by IL-12 [15,16]. Indeed, IFN-γ-deficient mice as well as knockout mice for IL-12p40, the large subunit of IL-12, were resistant to EAE [17-20]. However, further observations that mice deficient in IL-12p35, the smaller subunit of IL-12, and IL-12Rβ2 were susceptible to EAE [21,22] as well as data showing that the administration of IL-12 during the early phases of EAE suppressed EAE in an IFN-γ dependent manner [23], suggested that Th1 cells could not be responsible for the pathogenesis of MS. The discovery that IL-23 shares the p40 subunit with IL-12 clarifies these contradictory data [24]. Cua et al. demonstrated that IL-23 rather than IL-12 is crucial for EAE development by showing that IL-23p19, the smaller subunit of IL-23, deficient mice were resistant to EAE [25,26]. Data from Langrish et al. clearly defined the role of IL-23 in favouring EAE by driving and inducing the expansion of a novel Th subset producing IL-17 [26], designated Th17 cells [27,28].

The hallmark of Th17 cells is the production of the proinflammatory cytokine IL-17 (A and F) that affects the functions of a wide range of cells, enhances the secretion of other pro-inflammatory cytokines and chemokines and increases the activation of matrix metalloproteinases, thus contributing to the breakdown of BBB [29]. In the human system, Th17 differentiation can be mediated by IL- 6, TGF-β and IL-21, while IL-23 is critical in maintaining the Th17 phenotype [30-35]. Several data demonstrated that CD4+ Th17 subset exerts a central role in the pathogenesis of both EAE and MS. Increased numbers of Th17 cells have been found in the both inflamed CNS [36] and in the periphery of acute EAE [5] as well as in the CSF of MS patients during relapses [37]. High levels of IL-17A have been also detected in circulating leukocytes of MS patients with active disease [38], and higher IL-17A production has been correlated with the number of active plaques on magnetic resonance imaging [39]. All these data strongly support a pivotal contribution of Th17 cells in the pathology of MS [40].

Regulatory T cells (Tregs)

Tregs are negative regulators of T helper cell responses and contribute to T cell “anergy” and to the maintenance of self- tolerance, thus protecting against autoimmunity [41,42]. Tregs can be identified through their surface phenotypes and cytokine producing profiles. Tregs may be divided into two main subsets, natural Tregs (nTregs) and inducible Tregs (iTregs). The CD4+CD25+ FOXP3+ nTregs develop in the thymus and their TCR repertoire is skewed towards the recognition of self-antigens. In contrast, iTregs, originate from naive T cells in the peripheral lymph nodes, are either CD4+ or CD8+ and may or not express FOXP3 [43].

Dysfunctions or impairment maturation of Tregs have been observed in animal models of MS [44]. The presence of myelinspecific Tregs within the CNS during EAE highlights their role in the control of disease. Indeed, the accumulation and frequency of Tregs in the CNS has consistently been shown to correlate with recovery from EAE. However, myelin-specific Tregs were not sufficient to reduce the function of encephalitogenic effector T cells during the peak of EAE [45].

In MS, several reports have shown that human Tregs are functionally impaired, have decreased FOXP3 expression compared to healthy individuals, or have deficit in their maturation, or in their thymic emigration [44]. Reduced number or impaired suppressive functions of Tregs have been also found in the peripheral blood of MS patients [46-49]. Therefore, dysfunction in the number and/or functions of Tregs may concur to the immunopathogenesis of MS by decreasing the suppression of activated pathogenic immune cells (Figure 1).

Citation: Tuosto L. Targeting Inflammatory T Cells in Multiple Sclerosis: Current Therapies and Future Challenges. Austin J Mult Scler & Neuroimmunol. 2015;2(1): 1009.