T cells in vascular inflammatory diseases

Abstract

Inflammation of the human vasculature is a manifestation of many different diseases ranging from systemic autoimmune diseases to chronic inflammatory diseases, in which multiple types of immune cells are involved. For both autoimmune diseases and chronic inflammatory diseases several observations support a key role for T lymphocytes in these disease pathologies, but the underlying mechanisms are poorly understood. Previous studies in several autoimmune diseases have demonstrated a significant role for a specific subset of CD4(+) T cells termed effector memory T (TEM) cells. This expanded population of TEM cells may contribute to tissue injury and disease progression. These cells exert multiple pro-inflammatory functions through the release of effector cytokines. Many of these cytokines have been detected in the inflammatory lesions and participate in the vasculitic reaction, contributing to recruitment of macrophages, neutrophils, dendritic cells, natural killer cells, B cells, and T cells. In addition, functional impairment of regulatory T cells paralyzes anti-inflammatory effects in vasculitic disorders. Interestingly, activation of TEM cells is uniquely dependent on the voltage-gated potassium Kv1.3 channel providing an anchor for specific drug targeting. In this review, we focus on the CD4(+) T cells in the context of vascular inflammation and describe the evidence supporting the role of different T cell subsets in vascular inflammation. Selective targeting of pathogenic TEM cells might enable a more tailored therapeutic approach that avoids unwanted adverse side effects of generalized immunosuppression by modulating the effector functions of T cell responses to inhibit the development of vascular inflammation.

Keywords: ANCA-associated vasculitis; Kv1.3 channels; T lymphocytes; atherosclerosis; effector memory T cells; vascular inflammation.

Figure 1

Proposed pathophysiological mechanism of T cell mediated vascular inflammation. Vascular inflammation is initiated by a pro-inflammatory trigger such as an infection. Release of pro-inflammatory cytokines causes priming of neutrophils, up-regulation of adhesion molecules on endothelial cells, and an expansion of circulation effector T cells. Activation of primed neutrophils enhances vessel wall adherence and the transmigration capacity of the neutrophils. Production of reactive oxygen species and degranulation of fully activated primed neutrophils causes damage to vascular endothelial cells. This acute injury together with pro-inflammatory triggers elicits an innate inflammatory response that recruits T lymphocytes, which replace the neutrophils and either resolves or mediate the development of vasculitis. In this pro-inflammatory environment, the innate immune system with antigen-presenting cells (APCs) and T cells start to mediate the inflammatory response. Distinct cytokine patterns in combination with a defect in regulatory T (T_REG) cell function or frequency results in expansion of effector memory T (T_EM) cells. The dysbalance in the homeostasis of T_REG cells and T_EM cells, results in additional releases of pro-inflammatory cytokines promoting neutrophil priming and persistent activation of T_EM cells. Expanded circulating T_EM cells upregulate their killer immunoglobulin-like receptor (NKG2D) and interact with their ligand major histocompatibility complex class-I chain-related molecule A (MICA) on vascular endothelial cells. This event results in the migration of T_EM cells into target tissues, drive granuloma formation leading to tissues destruction in a perforin-dependent, and granzyme-dependent way, ending up in vasculitis. The T cell driven vascular inflammatory response is a multistep process and has different therapeutic possibilities. For this purpose, selective T_EM cell modulation might be beneficial to regulate the T_EM cell activity, proliferation, and migration. Other therapeutic options are modulation of T cell activation by interfering with co-stimulatory molecules, depletion of T cells, inhibition of T cell migration, or neutralizing secreted pro-inflammatory cytokines (This figure was created using Visi ScienceSlides^® Software).