Innate-adaptive immunity interplay and redox regulation in immune response

Abstract

Innate and adaptive immune cell activation and infiltration is the key characteristic of tissue inflammation. The innate immune system is the front line of host defense in which innate immune cells are activated by danger signals, including pathogen- and danger-associated molecular pattern, and metabolite-associated danger signal. Innate immunity activation can directly contribute to tissue inflammation or immune resolution by phagocytosis and secretion of biologically active molecules, or indirectly via antigen-presenting cell (APC) activation-mediated adaptive immune responses. This review article describes the cellular and molecular interplay of innate-adaptive immune systems. Three major mechanisms are emphasized in this article for their role in facilitating innate-adaptive immunity interplay. 1) APC can be formed from classical and conditional innate immune cells to bridge innate-adaptive immune response. 2) Immune checkpoint molecular pairs connect innate and adaptive immune cells to direct one-way and two-way immune checkpoint reactions. 3) Metabolic reprogramming during immune responses leads to excessive cytosolic and mitochondrial reactive oxygen species (ROS) production. Increased NADPH oxidase-derived extracellular and intracellular ROS are mostly responsible for oxidative stress, which contributes to functional changes in immune cells. Further understanding of innate-adaptive immunity interplay and its underlying molecular basis would lead to the identification of therapeutic targets for immunological and inflammatory disease.

Keywords: Adaptive immunity; Immune checkpoint; Immune interplay; Innate immunity; Reactive oxygen species.

Fig. 1

Innate-adaptive immunity interplay in immune response.A. Innate immune response. Immune recognition (MADS:MS and PAMP/DAMP:PRR) initiates innate immune response leading to pathogen elimination, adaptive immunity stimulation, and trained immunity via cytokine, chemokine, phagocytosis response, APC activation, and epigenetic reprogramming/metabolism rewiring, and contributes to tissue inflammation or repair. B. Adaptive immune response. Adaptive immunity determines tissue inflammation and repair, consisting of cell- and humoral-mediated immunity. Four signals are involved in cell-mediated immunity (Ag recognition, checkpoint, cytokine stimulation, and MADS recognition). CD40:CD40L is a representative immune checkpoint molecular pair. There are 2 types of humoral immune response (T cell-dependent and -independent). Three signals are described for T cell-dependent B cell immune response (Ag recognition, immune checkpoint and cytokine stimulation). B cell can also respond to Ag without the participation of Th cell in T cell-independent immunity.

Fig. 2

APC bridges innate-adaptive immune responses. A. APC bridges innate-adaptive immune responses. The initial process of immune response is immune recognition of innate immune cell or innate immune-like cell-mediated by MADS:MS or DAMP/PAMP:PRR recognition. Activated innate immune cells process antigens intracellularly and present them via MHCII molecules. This process is called APC formation and serves as a bridge between innate and adaptive immunity. APC presents antigen to T cell leading to T cell activation. B. Antigen presented by APC in atherosclerosis. Antigens presented by APC in atherogenesis are summarized based on literature searching.

Fig. 3

Immune checkpoint molecules in innate-adaptive immunity interplay. A. Immune checkpoint (signal 2) in regulating innate-adaptive immune response. We defined two types of immune checkpoints, one-way and two-way, based on signal 2 direction. The one-way immune checkpoint only involves forward signaling and directs to T cell activation or suppression. The two-way immune checkpoint involves forward and reverse signaling which modulates both innate and adaptive immunity by inducing TC activation/suppression and innate immune cell/APC activation/suppression. B. Thirty immune checkpoint molecular pairs regulate T cell and APC function. Thirty immune checkpoint molecular pairs and their functions are illustrated. Red color symbol describes the stimulatory molecular pair and green color symbol describes inhibitory molecular pairs. Stimulatory immune checkpoint molecular pair ligation leads to T cell/APC activation and differentiation, whereas inhibitory immune checkpoint molecular pair ligation leads to T cell/APC suppression and apoptosis. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Redox regulation in innate-adaptive immunity interplay. Elevated Intracellular or extracellular ROS production is a critical metabolic change in immune responses. A. Redox regulation and signaling in innate and adaptive immune cells. In response to various stimuli or disease condition, immune cells display increased extracellular and intracellular ROS induction which are associated with inflammatory molecular-cellular changes and effector responses. B. Oxidative stress-related MHC and checkpoint molecular changes in APC. APC activation is associated with increased ROS or ROS-derived products which leads to immune checkpoint activation and T cell response. C. Model of redox regulation in immune response. Danger signals activate NOX which is responsible for increased intracellular and extracellular ROS production in immune or immune-like cells. The redox regulation mediates innate and adaptive immune cell activation, inflammatory response, APC formation/activation, and TC response via modulating the expression of major histocompatibility complex and immune checkpoint molecules. D. NOX1/2/4 play major role in intracellular and extracellular ROS induction. Plasma membrane-located NOX1/2 activation results in extracellular ROS production which can be dismutated by SOD3 to form H₂O₂ and then be diffused into the cytosol via water channel AQP. NOX1/2 located in PM/ER/ES can be activated via PKC-induced P47phox phosphorylation, resulting in intracellular O₂^•- generation which can be dismutated by SOD1 to form H₂O₂. NOX1/2-derived H₂O₂ can activate Mt-K_ATP via PKC-ε signaling, leading to the K⁺ influx, decrease of Mt membrane potential (ΔΨm), and ETC-derived ROS production. O₂^•- generated from Mt-located NOX4 is released into Mt matrix and dismutated by SOD2 to H₂O₂ which then be transported into cytosol via AQP.

Fig. 5

Innate-adaptive immunity interplay and redox regulation in immune response. Danger signals (DAMP/PAMP/MADS) induce immune response firstly via innate immune cell activation which leads to cytokine/chemokine production, trained immunity, pathogen elimination, and APC activation. The activated APC interacts with Naïve CD8⁺ and Naïve CD4⁺ T cell and function as a bridge to connect the innate and adaptive immune systems. Immune checkpoint molecule pairs (signal 2) determine the stimulatory or inhibitory immune response on T cell and APC. In the course of immune cell activation, active metabolic reprogramming leads to redox regulation and increased intracellular and extracellular ROS production. This results in immune subset differentiation. Naïve CD8⁺ T cell differentiates into CTL which lyse infected and tumor cells. Naïve CD4⁺ T cell differentiates into inflammatory subsets Th1/2/9/17/22, anti-inflammatory subsets Treg, and Tfh subset which helps Naïve B cell/B2 to differentiate into a plasma cell and the memory cell. MC/MΦ are classical APC and can be differentiated into anti-inflammatory subsets (not listed) and pro-inflammatory subsets (CD14++CD16⁺, CD14⁺CD40⁺, CD1b + Ly6C+(m), M1, M4, Mox). Immune cell subsets produce distinguish effector molecules which contribute to tissue inflammation or repair.