Autoimmune disease is known to be caused by the dysregulated immune response mediated via self-antigen-specific T cells. Genetic and environmental factors such as infection have been proposed to explain the significant and sensitive immune response to self-antigens. However, it is not still clear how a few clones of self-reactive T cells can trigger significant tissue damage in autoimmune diseases. Recently, antigen non-related T cells have been shown to play a potential role in the pathogenesis of autoimmune diseases, as well as infection and cancer (1-3).
The antigen specificity of T cells is derived from T cell receptors (TCRs), which interact with antigen-derived peptide presented by the components of major histocompatibility complex (MHC) expressed on the surface of the antigen-presenting cells (APCs). Activated T cells express antigen-specific immunity via clonal expansion and differentiate into memory cells resulting in long-term immunity. However, antigen non-specific T cells are also involved in immune response because they can be activated independent of antigen (4-6). Such T cell activation is called “bystander activation”. During pathogen infection and inflammatory response, cytokines, toll-like receptors (TLRs), ligands and other immune mediators activate self-reactive T cells, which activate the autoimmune response (Fig. 1A). Besides, initial self-antigen-mediated inflammatory response including activation of self-antigen-specific T cells can also lead to bystander activation of other antigen-specific memory T cells, which secrete pathogenic inflammatory cytokines contributing to autoimmune diseases (Fig. 1B). Therefore, in this review, we summarize previous studies investigating bystander activation of T cells in various conditions and emphasize their potential role in autoimmune disease as well as infection and cancer.
The phenomenon of T cell activation without TCR signaling has been reported since the 1980s. In 1989, Yang
T cells are composed of different populations, each of which expresses unique surface markers and transcription factors. In the thymus, conventional T cells develop into CD4+ or CD8+ T cells with TCRs consisting of α and β chains responsible for antigen specificity. However, unconventional T cells such as γδ T cells carry TCRs with γ and δ chains instead of and, β chains. Natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are unconventional T cells with a limited diversity or specificity to the restricted group of antigens. They are usually localized in tissues such as liver and mucosa for tissue immunity but also present in the circulation.
Invariant NKT (iNKT) cells recognize lipid antigens such as α-galactosylceramide (α-GalCer) presented by MHC class I-like molecule CD1d (14). NKT cells can be divided into type 1 and type 2 NKT cells. Type 1 NKT cells carry CD1d-restricted semi-variant αβ TCR with limited β chain (Vβ8, Vβ7 or Vβ 2 in mice, and Vβ11 in humans), while type 2 NKT cells are known to contain a broader TCR repertoire. Leite-de-Moraes reported that splenic CD4+ NKT cells in MHC class II-deficient mice secreted IFN-γ without further stimulation after a single injection of IL-12 plus IL-18 (15). In 2008, it was reported that IL-17RB+ CD4+ NKT cells secrete IL-13 and Th2 chemokines upon stimulation with IL-25
Gamma delta (γδ) T cells are unique T cells carrying TCRs, each composed of γ and δ chains instead of α and β chains (14). They constitute about 4% of all T cells in the lymphoid tissue and are abundant in the skin and gut. Murine γδ T cells can be roughly divided into two types: IFN-γ+ and IL-17+ cells, depending on the type of cytokines they secrete (18). Haas
Mucosal-associated invariant T cells (MAIT cells) express semi-invariant αβ TCR and similar to other unconventional T cells have limited TCR diversity (Vα19–Jα33 and Vβ8 or Vβ6 in mice, Vα7.2–Jα33 and Vβ2 or Vβ13 in humans) (14). MAIT cells recognize microbial-derived vitamin B metabolites presented to β2M-associated MHC-related 1 (MR1) (20). MAIT cells are CD161+ Vα7.2+ CD8+ CD4− CD3+ T cells secreting effector cytokines independent of TCR. Compared with other T cell subsets, CD161high CD8+ T cells in human PBMC express IFN-γ more sensitively in response to IL-12 and IL-18 (21). In addition, IFN-γ synthesis was TCR-independent and not inhibited by cyclosporin A, which inhibits calcineurin in TCR signaling. In 2016, Wilgenburg
CD4 T cells, also known as T helper cells, can be divided into several types, such as Th1, Th2, Th17, and Treg. When they are activated, each effector CD4+ T cell type secretes specific cytokines following immune response. Interestingly, several studies show that CD4+ T cells can be activated even without TCR stimulation (23). In 1999, Gangappa
Multiple sclerosis (MS) is a chronic autoimmune disease mainly induced by uncontrolled infiltration of T and B cells into the central nervous system (CNS) resulting in inflammation and demyelination in the CNS. In experimental autoimmune encephalomyelitis (EAE), one of the murine models of MS, the activation or adoptive transfer of myelin-recognizing T cells such as myelin oligodendrocyte glycoprotein (MOG)-specific T cells is known to play a key role in demyelination. Although, MOG-specific T cells are required for tissue damage in CNS during EAE progression, surprisingly, most CNS-infiltrated T cells are unrelated to MOG antigen specificity (38-40). Non-myelin-specific T cells such as ovalbumin (OVA)-specific T cells increased the susceptibility to EAE by enhancing the number and function of APC in the CNS following injection of a synthetic peptide of myelin basic protein (MBP) (41). Toll-like receptors (TLRs) play an important role in innate immune activation; however, the loss of TLR2 and TLR4 in CD4+ T cells reduced disease symptoms in the EAE model, which regulates the production of IL-17, IL-21, RORγt, and IFN-γ (42, 43). In addition, TLR2, TLR4, and TLR9 are highly expressed on CD4+ and CD8+ T cells of patients with MS compared with healthy controls, and the proportion of cytokine-secreting TLR+ T cells are correlated with the degree of brain lesion (44). In addition, injection of LPS induces by-stander activation of MBP-specific T cells contributing to EAE in MBP TCR-transgenic mice, which requires physical contact with antigen-presenting cells via CD86 co-stimulation (45). Recently, our studies revealed that IL-1β and IL-23 contributed to bystander activation of OVA-specific Th17 cells, which turn pathogenic by producing IL-17A, IFN-γ, and GM-CSF. As a result, the augmented antigen-specific T cell response led to severe EAE symptoms (2). Collectively, multiple reports demonstrated the presence of nonmyelin-specific T cells in the CNS with significant effector functions contributing to autoimmune encephalomyelitis.
Rheumatoid arthritis (RA) is an autoimmune disease caused by the destruction of joint cartilage and bone. Autoreactive CD4+ T cells secrete cytokines resulting in the activation of osteoclasts and destruction of joint elements. Several studies investigating the factors triggering RA proposed bystander activation of T cells as one of the causes. In 2000, Tan
Type 1 diabetes (T1D) is an autoimmune disease caused by the selective destruction of insulin-producing β cells in the pancreas of islets of Langerhans. In 1998, Marc S. Horwitz
Bystander T cell activation has been observed in studies of infection. Tough
In 2006, Joncker
Various types of T cell populations such as NKT cells, γδ T cells, MAIT cells, and conventional CD4+ and CD8+ T cells can be induced to exhibit innate-like effector function via bystander activation. Although antigen-specific T cell response is a hallmark of the adaptive immune system, antigen non-related T cells proliferate significantly and synthesize effector cytokines in inflammatory tissues. During pathogen infection, antigen-specific T cells are activated by cytokines to reject tumors or to ensure protective immunity. In addition, in the absence of cognate antigen recognition, bystander activation of various types of T cells to secrete inflammatory cytokines can also facilitate the clearance of pathogen or tumor cells. Otherwise, bystander T cell function is of limited interest in understanding the mechanism of autoimmune disease pathogenesis. Few studies in RA and EAE suggest infiltration of antigen-nonrelated T cells into inflammatory tissues and synergistically contribute to autoimmune diseases. The detailed mechanisms of inflammatory infiltration of antigen non-specific T cells and regulation of their effector functions have yet to be elucidated. Based on the summary of previous studies, we propose the mechanism of autoimmune disease pathogenesis via bystander activation of either self-antigen-specific T cells or non-related T cells (Fig. 2). Further studies are needed to distinguish antigen-specific T cells from bystander-activated T cells to better understand disease pathogenesis. Collectively, the elucidation of bystander-activated T cell function along with antigen-stimulated T cells is required to understand the pathologic me-chanism of autoimmune disease and to develop novel drug candidates targeting autoimmune disease.
This research was supported by the Basic Science Research Program (NRF-2019R1A2C3006155) of the National Research Foundation funded by the Korean government.
The authors have no conflicting interests.