Innate Control of Adaptive Immunity: Beyond the Three-Signal Paradigm

Abstract

Activation of cells in the adaptive immune system is a highly orchestrated process dictated by multiples cues from the innate immune system. Although the fundamental principles of innate control of adaptive immunity are well established, it is not fully understood how innate cells integrate qualitative pathogenic information to generate tailored protective adaptive immune responses. In this review, we discuss complexities involved in the innate control of adaptive immunity that extend beyond TCR engagement, costimulation, and priming cytokine production but are critical for the generation of protective T cell immunity.

Figure 1

Linear and complex view of innate control of adaptive immunity. A. The three-signal paradigm: Purified PAMPs activate PRRs on dendritic cells (commonly used ex vivo source of APCs). Mature DCs present the associated antigen onto MHC molecules (signal 1) along with co-stimulation (signal 2) and innate cytokines (signal 3) to activate and differentiate naive T cells. Activated T cells undergo clonal expansion and produce their respective effector cytokines (measurable parameters), which we here referred to as productive immunity but may not necessarily provide required protection against a given pathogen. B. Beyond the three-signal paradigm: Successful generation of long-term protective immunity depends on the complex PAMPs and virulence factors associated with the pathogen, with additional inputs generated from route of infection and immune status of the host. All these parameters together are sensed by the innate immune cells and converted into meaningful information relayed to T cells. In addition to the three signals mentioned above, T cells responses are intricately modulated by specific assortment of innate cytokines (IL-1 or type I IFN family), commensal derived metabolites and tissue-specific parameters such as the innate cell type and stromal cell derived factors. All these signals together determine how the innate immune system instructs adaptive immune system to generate protective immunity against specific pathogens.