Peripherally Induced Regulatory T Cells: Recruited Protectors of the Central Nervous System against Autoimmune Neuroinflammation

Abstract

Defects in regulatory T cells (Treg cells) aggravate multiple sclerosis (MS) after its onset and the absence of Treg cell functions can also exacerbate the course of disease in an animal model of MS. However, autoimmune neuroinflammation in many MS models can be acutely provoked in healthy animals leading to an activation of encephalitogenic T cells despite the induction of immune tolerance in the thymus including thymically produced (t)Treg cells. In contrast, neuroinflammation can be ameliorated or even completely prevented by the antigen-specific Treg cells formed extrathymically in the peripheral immune system (pTreg cells) during tolerogenic responses to relevant neuronal antigens. This review discusses the specific roles of Treg cells in blocking neuroinflammation, examines the impact of peripheral tolerance and dendritic cells on a relevant regulation of neuroinflammation, and explores some of the most recent advances in elucidation of specific mechanisms of the conversion and function of pTreg cells including the roles of CD5 and Hopx in these processes.

‘Repair’ Treg Cells in Tissue Injury

“…Treg recruitment to the spinal cord parenchyma occurred at the subacute/chronic phase in the context of a spinal cord injury model, indicating that Tregs participate in the central nervous system (CNS) for neural maintenance and repair [38]. In line with this notion, Tregs were found to recruit protectors of the CNS against autoimmune neuroinflammation [39]. The important Treg-mediated repair tissue that has also been partially addressed is the delineation of bone regeneration in rheumatoid arthritis.…”

Dendritic Cells As Inducers of Peripheral Tolerance

“…However, thymically-produced tTreg cells may be overwhelmed by specific pro-inflammatory autoimmune activation; also, in some individuals, the development of self-antigen specific tTreg cells may be compromised [5, 10, 11, 16]. Similarly, in various animal models of autoimmune diseases, the autoimmune process can be initiated in healthy animals after immunization with specific self-antigens either in the presence of adjuvants or in the context of an introduced infectious agent, ultimately leading to the priming of the pre-existing self-reactive T cells [11, 17]. Overall, self-reactive T cells continue to persist in the peripheral immune system, and, for multiple reasons, thymically-imposed mechanisms of tolerance may fail to prevent a specific immune priming of such self-reactive T cells, ultimately leading to the autoimmune process [5, 10, 11, 17, 18].…”

“…Although cross-presented antigens acquired from various tissues may lead to deletion of CD8 + T cells, the tolerance spontaneously induced by DCs in this way may be particularly important for the maintenance of immune homeostasis to self- and oral antigens within the intestine [25–29]. In contrast, the spontaneous induction of mechanisms of peripheral tolerance including CD4 + T cell deletion, anergy and conversion of peripheral (p)Treg cells in response to antigens from organs that are more insulated from the immune system (such as the central nervous system (CNS)), may be less efficient [17]. Therefore, spontaneously induced peripheral tolerance induced by DCs may not prevent autoimmune responses against the CNS and other organs whose antigens are not sufficiently available for the specific induction of mechanisms of peripheral tolerance.…”

Regulatory T Cells: Pathophysiological Roles and Clinical Applications

“…Data from Kasahara et al 17 and some genes important for Treg function, and these defects may contribute to the onset of disease. 85 In a mouse model of experimental autoimmune encephalomyelitis, which mimics MS, symptoms worsen as a result of the depletion or deficiency of Tregs. 83 In mice lacking T cells, remyelination is delayed after lysolecithin injection, suggesting that T cells are required for remyelination of the central nervous system.…”