The ambiguity in immunology

Abstract

In the present article, we discuss the various ambiguous aspects of the immune system that render this complex biological network so highly flexible and able to defend the host from different external invaders. This ambiguity stems mainly from the property of the immune system to be both protective and harmful. Immunity cannot be fully protective without producing a certain degree of damage (immunopathology) to the host. The balance between protection and tissue damage is, therefore, critical for the establishment of immune homeostasis and protection. In this review, we will consider as ambiguous, various immunological tactics including: (a) the opposing functions driving immune responses, immune-regulation, and contra-regulation, as well as (b) the phenomenon of chronic immune activation as a result of a continuous cross-presentation of apoptotic T cells by dendritic cells. All these plans participate principally to maintain a state of chronic low-level inflammation during persisting infections, and ultimately to favor the species survival.

Keywords: ambiguity; autoimmunity; cancer; homeostasis; inflammation.

Figure 1

Protective and harmful B cell responses leading to infection resolution. Upon infection by a given pathogen (i.e., a virus), innate immunity is firstly elicited (1) and acts both to promptly control the pathogen spread and to cooperate with the virus-related antigens (presented by professional APCs) for the priming of the adaptive immunity harm (2). Both pathogen-specific antibodies (particularly, the non-neutralizing, which represent the majority of antibodies generated in response to a given pathogen!) and autoantibodies (that can be generated via cross-reactivity or bystander mechanisms) can form immune complexes (ICs) and produce damage through the cooperation with the innate immune system (macrophages, complement factors, inflammatory cytokines…) (3). However, neutralizing, non-neutralizing virus-specific B cells, as well as the autoreactive, act in concert to fight the pathogen: the neutralizing in an antigen-specific manner, the non-neutralizing and autoreactive in a bystander manner via the activation of the phagocytic system by ICs resulting in the amplification of the inflammatory responses (acute disease). This inflammatory storm is self-limited, when the pathogen is cleared.

Figure 2

Protective and harmful T cell responses leading to infection resolution. Recovery from infections is dependent on the efficient priming of T cells by professional APCs (DCs) working in concert with other innate immune cells. The efficiency of DCs in migrating from inflamed tissues to lymph nodes, in presenting antigens, and in T cell priming is in turn dependent on the engagement of different types of DC sensors by pathogens (such as TLRs engaged by PAMPs). In addition (CD4⁺) Th1 cell polarization (dashed arrows) requires the presence of IFN-γ generally donated by NK cells, and IL-12, produced by DCs. (CD4⁺) Th2 cell polarization (dotted arrows) requires the presence of IL-4 particularly produced by basophils. Whereas (CD4⁺) Th17 cell polarization (arrows with dashes and dots) requires the presence of several cytokines, such as TGF-β, IL-6, IL-1 (particularly produced by monocytes and endothelial cells), and IL-23 (mainly produced by DCs). In all cases, the functional activity of DCs, T, or B cells is increased by the interaction between CD40, expressed by both DCs and B cells, and CD40 ligand (L), expressed by activated T cells. Then Th1 cells display protective activity against intracellular pathogens (i.e., viruses…), via both IFN-γ production (antiviral activity) and by cooperating with B cells producing IgG1 (in humans) or IgG2 (in mice) neutralizing antibodies. Th2 cells are protective against extracellular pathogens, such as helminthes, via the production of a series of cytokines (e.g., IL-4, IL-5, IL-13) addressed to provoke “allergic-like” hypersensitivity (obtained via the recruitment of various cells, including eosinophils and mast-cells) and production of protective IgE antibodies by B cells. Th17 cells seem to be important in fighting extracellular pathogens, such as fungal infections. (CD8⁺) Cytotoxic T lymphocytes (CTLs) directly kill infected cells via the recognition of class I molecules expressing pathogen peptides. In any case, activated T cells can eliminate the pathogen via the establishment of a severe inflammatory disease. T_reg cells control exaggerated responses or the emergence of autoreactive lymphocytes.

Figure 3

The balance between CD40L⁺ and CD40L⁻ apoptotic cells during cross-presentation dictates induction or tolerance of T cell responses. (A) Apoptotic T cells expressing CD40L can directly provide to DCs both (apoptotic cell-derived) self antigens and the necessary maturation stimuli for T cell priming. (B) Under conditions in which the CD40L⁺ apoptotic T cells are overwhelmed by the CD40L⁻ apoptotic cells (i.e., under normal conditions or when an inflammatory process is terminated), the latter will be unable to provide the appropriate signals to DCs, which will deliver tolerance signals to autoreactive T cells, even though they carry apoptotic cell-derived peptides.

Figure 4

Chronic low-level inflammation as an advantage for the long-term human survival. Several mechanisms induced by both persistent pathogens (e.g., escape by pathogen mutations, pathogen-related immune subversion) and the host [e.g., PD-1-dependent T cell exhaustion, Regulatory T (T_reg) cells] contribute to the maintenance of chronic inflammatory diseases, by down-modulating DC functions, T and B cell priming, generation of memory cells, and ultimately differentiation of terminal effector cells. T_reg cells can be represented by the following: (a) CD4⁺CD25⁺Foxp3⁺ T_reg cells, which suppress via cell–cell contact, IL-2 capture to effector cells, TGF-β production, etc.; (b) T_reg cells producing immunosuppressive cytokines (e.g., IL-10, TGF-β). PD-1 is upregulated on both responder and T_reg cells and upon contact with PD-L1/2 limits both T effector memory (T_EM) cell responses and excessive T_reg cell function, respectively. The resulting contra-regulation of T_reg cells will have an important role to limit excessive suppression of immune responses allowing the control of the viral spread, at the cost of the maintenance of the chronic low-level liver immunopathology. This mechanism establishes a long-lasting survival of the host.

Figure 5

Chronic inflammatory diseases as the “Yin and Yang” of the immune system. Under conditions in which the immune system has been bypassed by persistent pathogens, chronic low-level inflammation guarantees long-term survival of the majority of infected individuals in spite of pathogen persistence. The imbalance of the homeostatic mechanisms maintaining chronic inflammation may degenerate into severe “side effects” (such as autoimmune disorders or tumors) in some individuals. However, these side effects are considered irrelevant in terms of the survival of the species.

Figure 6

Chronic immune activation as a result of cross-presentation of apoptotic T cells. During severe inflammatory processes, chronic immune activation may be in part maintained by a vicious spiral, which may be initiated by activated lymphocytes (e.g., specific for persistent microbial antigens or self antigens) undergoing apoptosis upon they performed their effector functions. These apoptotic cells are cross-presented by DCs, which cross-prime a huge repertoire of autoreactive T cells specific for a multitude of apoptotic cell-associated epitopes. Apoptotic antigen-specific T cells participate to the maintenance of chronic immune activation via their effector performances, then they will undergo apoptosis, and the resulting apoptotic cells will be cross-presented by DCs that will cross-prime new waves of apoptotic antigen-specific T cells, and so on.