Tissue-Based Class Control: the Other Side of Tolerance
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PERSPECTIVES the model did not offer any clues as to how ESSAY one effector class might be chosen over another, as it was designed to cover only the Tissue-based class control: the other immune system’s first decision (whether to respond or not). It proposed that per- side of tolerance turbed tissues initiate immune responses by sending alarm signals that activate local antigen-presenting cells (APCs), whereas Polly Matzinger and Tirumalai Kamala healthy tissues display their own antigens Abstract | In this Essay, we offer a new perspective on how immune responses are or allow ‘resting’ APCs to display those antigens to induce peripheral tolerance. In regulated. We do not cover how they are turned on and off, but focus instead on effect, this model suggested that turning the second major aspect of an immune response: the control of effector class. immune responses on or off was the pre- Although it is generally thought that the class of an immune response is tailored to rogative of the tissues. It takes only a small fit the invading pathogen, we suggest here that it is primarily tailored to fit the step to suggest that tissues may also control tissue in which the response occurs. To this end, we cover such topics as the nature the effector class, such that the class of an immune response is tailored to the tissue in of T helper (T ) cell subsets (current and yet to be discovered), the nature of H which it occurs, rather than to the invading privileged sites, the difference between oral tolerance and oral vaccination, why pathogen. The basics of this idea were out- 12,14 the route of immunization matters, whether the TH1‑type response is really the lined in two earlier articles . In this Essay, immune system’s primary defense, and whether there might be a different role for we describe the idea more fully, suggesting some regulatory T cells. mechanisms by which tissues could carry out this function, describing some well- known immunological phenomena in light When confronted with a potential threat, organisms; and the ‘innate’ receptors, such of this view, and pointing out the possibility the immune system faces two decisions: as the Toll-like receptors (TLRs) and NOD- that a complete definition of the immune first, whether to respond or not, and second, like receptors (NLRs), are so promiscuous system should perhaps include every tissue what kind of response to make. The first that they don’t distinguish between ligands in the body. decision has fascinated immunologists for from different phyla, or between pathogen- decades, sparking several theories and much derived and self-derived alarm signals6–9. Class and T helper cell subsets experimental work, most of which rests on Although current data suggest that TLR5 Let us start by defining what we mean by the assumption that the immune system and NOD2 (nucleotide-binding oligomeriza- immune effector class. Although the term responds to ‘foreign’ antigens, and that tion domain protein 2) may be fairly specific, “class” has historically been used to define maintaining self tolerance is a matter of con- it would be difficult to use even these recep- different antibody isotypes (such as IgM trolling autoreactive T and B cells. But deal- tors to make decisions about effector class. and IgG), we prefer a definition that also ing with autoreactive lymphocytes is only NOD2 does not distinguish between intra- includes the participating cells. Thus, each half of the problem. Even in the absence of cellular and extracellular bacteria, as it binds effector class combines a particular set of any autoreactivity, the wrong immune effec- muramyl dipeptide, a component of almost helper cells and the antibodies and effec- tor class can completely destroy a tissue1–5. all bacterial cell walls10. Similarly, TLR5 tor cells that they promote. Currently, three The control of effector class, however, has binds the flagella of both intracellular patho- main subclasses are generally accepted. had little theoretical input. Students gener- gens (such as Listeria monocytogenes) and TH1-type responses consist of T cells that ally learn that the immune system matches extracellular pathogens (such as Escherichia produce interleukin-2 (IL-2), interferon-γ the effector class to the pathogen that it is coli and Pseudomonas aeruginosa)11, whereas (IFNγ) and tumour necrosis factor (TNF), as fighting (for example, making IgE against it does not bind the flagella of several well as B cells that make complement-fixing worms, and cytotoxic T lymphocytes (CTLs) other important pathogens (including IgG antibodies, CTLs, activated natural killer against viruses and intracellular bacteria). Helicobacter pylori, Staphylococcus aureus (NK) cells and macrophages that produce 11 But it is not easy to see how the immune and Campylobacter jejuni) . free oxygen radicals. TH2-type responses system could discriminate between worms, So, what controls the effector class of an consist of T cells that produce IL-4, IL-5, viruses or intracellular versus extracellular immune response? The idea that it might be IL-13 and IL-10, B cells making IgE and bacteria, as T cell receptors bind peptide– the tissues, rather than the immune system, IgG1, macrophages that express arginase, MHC complexes; B cell receptors bind has grown slowly over the 13 years that we and the influx of eosinophils. TH17-type small epitopes on proteins, carbohydrates have been studying immunity from the per- responses consist of T cells that produce and lipids that are present in most living spective of the danger model12,13. Initially, IL-17 and the influx of neutrophils. NATURE REVIEWS | IMMUNOLOGY VOLUME 11 | MARCH 2011 | 221 © 2011 Macmillan Publishers Limited. All rights reserved PERSPECTIVES However, there have long been clues response, it has limited our ability to recognize There is, however, a world of differ- that this is an oversimplification. Human the potentially enormous diversity of immune ence between data and interpretations. The T cells, for example, often show non-classical responses. If we were to stop consigning interpretation that immunity cannot occur cytokine expression patterns, and it took TH cells to a small group of numbered subsets, in privileged sites makes little evolutionary a long time to persuade researchers work- but instead name them by what they produce sense. These tissues are wet, warm and full of ing with human cells to adopt the TH1- and (as is done for TH17 cells) or by the responses nutrients. Without protection by the immune 15 TH2-type classifications. In mice, Kelso they promote (as is done for follicular helper system, wouldn’t they promptly be exploited found that micromanipulated single T cells T cells), we would uncover the possibility that by pathogens? Luckily, other interpretations do not stably make TH1- or TH2-type cytokine there are a large number of differentiation exist. Streilein’s work on the eye reveals a ‘cassettes’. She suggested that the TH1- and paths that TH cells can take. We would suggest much more interesting picture. TH2-type patterns are only the extremes of a that each particular effector cell (such as each The eye is a complex tissue, containing multidimensional continuum; that individual type of B cell, CTL, NK cell, macrophage, eosi- delicate specialized cells that cannot sur- T cells normally make only a small number nophil, neutrophil and basophil) is controlled vive a full-blown TH1-type or delayed-type of stochastically produced cytokines; and by a particular set of secreted and membrane- hypersensitivity (DTH) response. It protects that populations of T cells can diversify to bound signals (from TH cells and from other itself by a process Streilein called “anterior produce any number of different cytokine sources) and can be combined with any chamber-associated immune deviation”27, combinations. More recently, O’Shea and other effector cell to make a wide variety of in which cells lining the anterior chamber Paul16 proposed a somewhat similar sce- carefully tailored immune responses. secrete cytokines — transforming growth nario, but these views are far from universal. Given the existence of such a variety of factor-β (TGFβ), vasoactive intestinal pep- For example, Pulendran’s and Oppenheim’s effectors, and the TH cells that facilitate them, tide (VIP) and α-melanocyte stimulating groups found that dendritic cells (DCs) what determines the ultimate effector combi- hormone (αMSH) — that suppress TH1-type stimulated by Porphyromonas gingivalis- nation that arises in any particular immune and DTH responses and increase the activity 17 28 (TABLE 1) derived lipopolysaccharide (LPS) or by response? We were drawn to the possibility of regulatory T (TReg) cells . 18 eosinophil-derived neurotoxin induce TH that this is the responsibility of the tissues Although this appears to be immune sup- cells that secrete IL-5 but not IL-4 (the signa- by two old immunological phenomena: pression, a closer look suggests something ture TH2-type cytokine). In addition, Prussin immune-privileged sites and oral tolerance. different. TGFβ, VIP and αMSH all promote and colleagues19 found two different subsets IgA production29–32, but IgA cannot reject a Immune-privileged sites of TH cells in atopic patients, some of which transplant. So if we measure ocular immu- produce IL-5 but not IL-4. Nevertheless, Immune-privileged sites are organs in which nity only by transplant rejection, and ignore rather than postulate the existence of a TH cell allogeneic transplants are not rejected. the perfectly functional IgA response, we call that did not fit into the standard categories, all Neonatal hearts, for example, are rejected it “tolerance”, “deviation”, “suppression” or of these authors called these IL-5-producing when transplanted under the skin or kidney “regulation”. But this is none of those things. 20 cells “TH2 cells”. capsules of adult recipients , but survive It is simply a class of response that protects We believe it is time to follow Kelso’s lead indefinitely if placed into the anterior chamber the eye without destroying it.