The role of CD8 suppressors versus destructors in autoimmune central nervous system inflammation

Summary

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) of putative autoimmune origin. Recent evidence indicates that MS autoimmunity is linked to defects in regulatory T-cell function, which normally regulates immune responses to self-antigens and prevents autoimmune diseases. MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have long been regarded as a CD4⁺ T-cell-mediated autoimmune disease. Studies addressing the role of CD8⁺ T cells, however, have only recently begun to emerge. Pathogenic function was attributed to CD8⁺ T cells because of their abundant presence or oligoclonal repertoire within MS lesions. However, CD8⁺ T cells appeared to have important regulatory functions, as demonstrated in EAE or human MS studies. We here review the contribution of CD8⁺ T cells to inflammation and immune regulation in CNS autoimmunity. The knowledge of distinct CD8⁺ T-cell populations exerting destructive versus beneficial functions is summarized. The long-term goal is to delineate the exact phenotypic and functional characteristics of regulatory CD8⁺ T-cell populations (natural as well as inducible) in humans. This knowledge may help to further develop concepts of reconstituting or enhancing endogenous mechanisms of immune tolerance in future therapeutic concepts for MS.

Introduction

Multiple sclerosis (MS) is a central nervous system (CNS) disorder characterized by inflammation, demyelination, and axonal damage [1]. A complex interplay between genetic and environmental factors, as well as an impaired immune balance, contributes to disease susceptibility and course. Several studies document an elevated frequency of macrophages and autoreactive T lymphocytes in an activated state [2], as well as high titers of serum and cerebrospinal fluid (CSF) antibodies against multiple viral and nonviral antigens [3]. Increased levels of general “immune reactivity” are accompanied by evidence for dysfunctions in several immunoregulatory immune subsets in MS patients (e.g., suppressor cells) [4], [5].

MS has long been considered a prototypic CD4⁺ T helper-1 (Th-1)-mediated autoimmune disease [1], [6]. Only recently has the importance of CD8⁺ T cells in the pathogenesis of CNS autoimmunity emerged. In some models of experimental autoimmune encephalomyelitis (EAE), CD8⁺ T cells convincingly served as beneficial regulators of pathology and clinical severity [7], [8], [9], [10]. Other EAE models reported CD8⁺ T cells were destructive effector elements relevant for the onset, severity, and extent of CNS pathology [11], [12], [13], [14]. An increasing number of human studies of MS patients report CD8⁺ T cells are key players involved in disease pathogenesis: CD8⁺ T cells outnumber CD4⁺ T cells in MS brain tissue [15], [16] and the number of CD8⁺ T cells and macrophages correlates with the extent of axonal damage in MS lesions [17], [18]. In contrast to CD4⁺ T cells, CD8⁺ T cells demonstrate oligoclonal expansions in the MS brain and CSF [19], [20], [21], [22], [23]. Expanded CD8⁺ T-cell clones exist in peripheral blood as, well as in the CNS, and persist over time [20]. Furthermore, distinct CD8⁺ T-cell clones in the CNS exist in different regions of MS brain specimens, further supporting their putative pathogenetic relevance [23], [24]. The detrimental function of CD8⁺ T cells is further supported by their ability to kill oligodendrocytes as well as neuronal cells [18], [25]. However, the antigen(s) or immunodominant epitopes recognized by these CD8⁺ T cells are yet to be determined.

Over the past years, several myelin sheath components such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), or proteolipid protein (PLP) were identified as immunologically relevant antigens (Ag), possibly associated with pathogenic autoimmunity in MS patients. Autoreactive CD4⁺ and CD8⁺ T cells recognizing these Ag as targets are believed to be crucial in the initiation and maintenance of CNS autoinflammation, resulting in myelin destruction and neural damage. The existing peripheral regulation of immune responses dampens potential pathogenic autoimmunity. This natural regulatory mechanism of healthy individuals seems to be impaired in patients with MS. Although the role of autoreactive versus regulatory CD4⁺ T cells has been the subject of intense studies over the past 2 decades, autoreactive versus regulatory CD8⁺ T cells have received much less attention.

This review summarizes our current knowledge regarding the role of CD8⁺ T cells in CNS autoimmunity. Studies in animal models have elegantly demonstrated both effector and regulatory roles of CD8⁺ T cells. In the cascades of immunoregulatory and destructive inflammatory events during MS, evidence for both functions has been described. However, many open questions exist in relation to the phenotypic and functional characteristics of natural and inducible CD8⁺ regulatory T cells. Further studies are required to demonstrate the relevance of CD8⁺ regulatory T cells for the etiopathogenesis or treatment of MS.