Bystander CD4+ T cells: crossroads between innate and adaptive immunity

Abstract

T cells are the central mediators of both humoral and cellular adaptive immune responses. Highly specific receptor-mediated clonal selection and expansion of T cells assure antigen-specific immunity. In addition, encounters with cognate antigens generate immunological memory, the capacity for long-term, antigen-specific immunity against previously encountered pathogens. However, T-cell receptor (TCR)-independent activation, termed "bystander activation", has also been found. Bystander-activated T cells can respond rapidly and secrete effector cytokines even in the absence of antigen stimulation. Recent studies have rehighlighted the importance of antigen-independent bystander activation of CD4⁺ T cells in infection clearance and autoimmune pathogenesis, suggesting the existence of a distinct innate-like immunological function performed by conventional T cells. In this review, we discuss the inflammatory mediators that activate bystander CD4⁺ T cells and the potential physiological roles of these cells during infection, autoimmunity, and cancer.

Fig. 1. Antigen-specific vs. bystander T-cell activation.

a Antigen-specific T-cell activation requires three distinct signals. Signal 1 is antigen-specific signaling mediated by T-cell receptor (TCR) engagement of pathogenic peptides presented by major histocompatibility complex (MHC) molecules. Signal 2 is costimulatory signaling, which is mainly mediated by the interaction of CD28 with one of the B7 molecules (CD80 and CD86). Signal 3 is polarizing signaling mediated by various cytokine milieus produced by dendritic cells. b In contrast, bystander T-cell activation is the concept of T-cell activation independent of antigen stimulation. Bystander-activated T cells can respond rapidly to inflammatory mediators (cytokine and TLR signaling) in a TCR-independent manner. TLR2 Toll-like receptor 2, TLR4 Toll-like receptor 4.

Fig. 2. Stimulatory molecules for antigen-independent bystander activation and functioning of CD4⁺ T cells.

Effector/memory CD4⁺ T cells (T_H1, T_H2, and T_H17) can undergo bystander activation by directly responding to inflammatory cytokines and TLR agonists. These signals induce effector cytokine production that promotes important pathological responses in autoimmunity and pathogen infections. Naïve CD4⁺ T cells can also be activated in a TCR-independent manner under the influence of cytokines such as IL-2, IL-18, and IL-27. Bystander activation of naïve CD4⁺ T cells can promote immunosuppressive functions that regulate autoimmune pathogenesis. IL interleukin, IFN-γ interferon-γ, GM-CSF granulocyte-macrophage colony-stimulating factor, PD-L1 programmed death-ligand 1, LPS lipopolysaccharide, T_H1 T-helper 1, T_H2 T-helper 2, T_H17 T-helper 17, T_N naïve CD4⁺ T cell.

Fig. 3. IL-1β and IL-23 induce pathogenic function in bystander-activated memory-like CD4⁺ T cells in autoimmune neuroinflammation.

IL-1β and IL-23 induce innate-like pathogenic function in memory-like CD4⁺ T cells that are not specific for myelin. Along with myelin-specific effector T cells (T_H1 and T_H17), bystander memory-like CD4⁺ T cells contribute to the development of autoimmune pathogenesis by increasing IL-17A, IFN-γ, and GM-CSF levels in the CNS. Thus, bystander-activated memory-like CD4⁺ T cells responding to IL-1β and IL-23 perform a pathogenic role in an antigen-independent manner in autoimmune encephalomyelitis. IL interleukin, IFN-γ interferon-γ, GM-CSF granulocyte-macrophage colony-stimulation factor, IL-1R1 interleukin-1 receptor type 1, IL-23R interleukin-23 receptor, RORγt RAR-related orphan receptor gamma, CCR6 chemokine receptor 6, T_H1 T-helper 1, T_H17 T-helper 17, CNS central nervous system.