Robustness trade-offs and host-microbial symbiosis in the immune system

Abstract

The immune system provides organisms with robustness against pathogen threats, yet it also often adversely affects the organism as in autoimmune diseases. Recently, the molecular interactions involved in the immune system have been uncovered. At the same time, the role of the bacterial flora and its interactions with the host immune system have been identified. In this article, we try to reconcile these findings to draw a consistent picture of the host defense system. Specifically, we first argue that the network of molecular interactions involved in immune functions has a bow-tie architecture that entails inherent trade-offs among robustness, fragility, resource limitation, and performance. Second, we discuss the possibility that commensal bacteria and the host immune system constitute an integrated defense system. This symbiotic association has evolved to optimize its robustness against pathogen attacks and nutrient perturbations by harboring a broad range of microorganisms. Owing to the inherent propensity of a host immune system toward hyperactivity, maintenance of bacterial flora homeostasis might be particularly important in the development of preventive strategies against immune disorders such as autoimmune diseases.

Figure 1a

Nested bow-tie architecture in immune system. Salient features of the immune system network are nested bow-tie structures and extensive feedback loops. (A) The bow-tie structure of intercellular interactions. The CD4+ T-cells are the hub of this interaction network. Various stimuli from pathogens are transmitted to dendritic cells (DC) that polarize CD4+ T-cells. Stimuli trigger the differentiation of naïve CD4+ T-cells and effector cytokine releases to follow. The whole behavior of this subsystem is controlled by complex signal transductions, and the cytokine network has adapted to the pathogenic environment to which it was exposed during evolution. Upon recognition of appropriate peptide–MHC complex and/or cytokine stimuli, naïve CD4+ T-cells polarize into either Th1, Th2, or Tr1 cells depending upon the cytokine stimuli (Moser and Murphy, 2000; Luther and Cyster, 2001; Murphy and Reiner, 2002) that are provided by polarized DC and a variety of innate immune cells (Kapsenberg, 2003). Th1 cells are induced by IFN-γ, IL-12, and IL-18, and secrete IFN-γ and IL-2, whereas Th2 cells are induced by IL-4 and secrete IL-4, IL-5, IL-13, and IL-10 (Abbas et al, 1996). Chromatin remodeling by GATA3 and T-bet is pivotal in Th1/Th2 polarization (Murphy and Reiner, 2002). Effector cytokines secreted from Th1 and Th2 cells affect various cells. For example, IFN-γ activates B-cells to secrete IgG2a and IgG3, IL-2 activates cytotoxic T lymphocytes (CTL), and IL-4 and IFN-γ mutually inhibit the growth of Th1 and Th2 T-cells, respectively (Liew, 2002). Among these cytokines, IL-2 plays an important role in shaping the dynamics of T-cell response because it promotes growth and activation of CD4+ CD25+ regulatory T-cells (Horak et al, 1995), which suppress autoreactive T-cells whether Th1 or Th2 (Shevach, 2002; Malek and Bayer, 2004). The source of IL-2 involved in CD4+ CD25+ T-cell activation has yet to be fully determined, but DC (Granucci et al, 2001) and autoreactive T-cells (Malek and Bayer, 2004) are considered to be involved. CD4+ CD25+ regulatory T-cells are considered to interact with mature DC and suppress helper and effector T-cell activities by an as yet unidentified mechanism (Mills, 2004). Th3 and Tr1 are induced by IL-4 in the presence of TGF-β and IL-10, respectively (Weiner, 2001). Tr1 may also be induced by immature DC or IL-10-modulated DC under TGF-β stimulation (Mahnke et al, 2002; Kapsenberg, 2003). Tr1 secretes IL-10 and TGF-β in a CTLA-4-dependent manner (Roncarolo et al, 2001) and Th3 secretes TGF-β. Repeated stimulation of naïve T-cells in the presence of IL-10 induces Th1 T-cells, and a high dose of IL-10 suppresses the growth of both Th1 and Th2 cells (Read and Powrie, 2001). The mechanism of suppression of CD4+ CD25+ T-cells is actively being investigated, but is considered to involve TGF-β release and binding of CTLA-4 to CD80 and CD86 on effector T-cells (von Boehmer, 2005). The negative feedback loop is mediated by Tr1 and Th3, and CD4+ CD25+ regulatory T-cells constitute feedforward control via mature DC and negative feedback control via autoreactive T-cells that are critical in the proper control of adaptive immune response to prevent autoimmune diseases.

Figure 1b

(B) The bow-tie architecture also exists at the signal transduction level. There are bow-tie structures in the TLR signaling network and adaptive immunity where antigen presenting and recognition is the hub of the network. APCs express a diverse range of receptors to recognize a wide variety of pathogens via PAMPs, etc. Signaling pathways and capturing processes converge into a smaller variety of core processes. For TLRs, only a handful of adaptor proteins and kinases mediate the signaling process that results in diverse responses including cytokine release, transcription, and other events. The innate immune system comprises TLRs and their downstream cascades that form the characteristic shape of the network called a bow-tie, or hour-glass, structure (Csete and Doyle, 2004; Kitano, 2004). A wide variety of pathogens and their molecules are represented by much smaller numbers of ligands, called PAMPs, recognized by IL-1R and 10 TLRs (Akira et al, 2001; Medzhitov, 2001). Only a handful of adaptor proteins, such as MyD88, MAL/TIRAP, TRIF, and TRAM, and two primary kinases (TBK1 and IRAK) mediate various responses and trigger massive changes in a broad range of transcription of target genes including secretion of cytokines and chemokines (Beutler, 2004). MyD88 has special importance as it constitutes a non-redundant core element of the main bow-tie network. Although there are collateral pathways such as MyD88-independent pathway, MyD88 is largely responsible for activation of TLR-mediated responses. Collateral pathways play roles in modulating different responses. This is a versatile architecture that enables organisms to evolutionarily add a new kind of receptor for new molecular signatures that eventually activate TBK1 and IRAK to bring about some responses. This is a bow-tie architecture at the signaling pathway, and exists in a broad range of somatic cells, but most saliently in macrophage and DC. In this bow-tie structure, there are nested bow-tie structures as well as positive feedback loops. For example, NF-κB and TNF form bow-tie structures having extensive input signals and changes in transcription and cytokine production (Li and Verma, 2002). Positive feedback loops involving NF-κB play an important role in the dynamics of the immune system in boosting innate immune response. An antigen-processing and presentation process captures a variety of peptides and presents them on MHC-I or MHC-II molecules that are recognized by TCRs. This antigen presentation and recognition part is a critical core process in adaptive immunity. A breach in proper presentation and recognition leads to improper immune reactions such as autoimmune diseases. Details of TLR signaling network are reported elsewhere (K Oda and H Kitano, in preparation).

Figure 2

Bacterial flora biodiversity improves robustness against environmental perturbations. (A) Upon changes in environmental conditions, such as changes in types of foods and pathogens, the host that can accommodate highly diverse bacterial flora is able to cope with such changes by composition changes of bacterial flora. (B) The host that only allows a narrow set of bacteria, hence low biodiversity bacterial flora, may not be able to cope with changes in food compositions and pathogens. This results in failure to digest certain types of foods and invasion of pathogenic bacteria to the host tissues.