Rethinking immunology

doi:10.1126/science.abj5637

GSTDTAP > 气候变化

DOI	10.1126/science.abj5637
	Rethinking immunology
	Carl Nathan
	2021-07-16
发表期刊	Science
出版年	2021
英文摘要	The cytokine interferon-γ (IFN-γ), when released by lymphocytes, augments the capacity of macrophages and other host cells to kill certain intracellular protozoa, bacteria, and viruses ([ 1 ][1]–[ 3 ][2]). However, the function of most of the hundreds of genes induced by IFN-γ is unknown, and biochemical mechanisms of pathogen inactivation are incompletely understood. On page 296 of this issue, Gaudet et al. ([ 4 ][3]) identify an effector mechanism in the human immune system: production of IFNγ–induced apolipoprotein L3 (APOL3) in epithelial cells, endothelial cells, and fibroblasts that acts like a detergent, extracting lipids from membranes of bacteria in the cytosol, killing the bacteria. Not only does APOL3 dissolve a biophysical boundary—the bacterial inner membrane—but the findings of Gaudet et al. help dissolve conceptual boundaries about the composition of the immune system. In 1882, Metchnikoff launched the field of immunology with a microscope, a thorn, and a starfish. Seeing cells gather where the thorn punctured the larva, he declared that phagocytic cells defend the host from invading microbes. Ehrlich favored soluble factors. By the 1950s, the paradigm was set: Both cells and soluble factors are required; the immune cells are macrophages, granulocytes, and lymphocytes; the soluble factors are chiefly antibodies and proteins collectively called complement because they are needed to lyse cells that antibodies tag for destruction. From the mid-1970s, immunologists distinguished dendritic cells from macrophages and denominated lymphocyte subsets, but the list of cell types in the immune system remained restricted. That the liver is the major source of complement and other host defense proteins did not earn hepatocytes membership in the immune system. The boundary between what is and is not part of the immune system has recently sprung more holes with the recognition that besides the liver, the nervous system ([ 5 ][4], [ 6 ][5]), epithelia ([ 6 ][5]–[ 8 ][6]), erythrocytes ([ 6 ][5]), and microbiota ([ 7 ][7]–[ 9 ][8]) are key contributors to mammalian immunity. Gaudet et al. further integrate diverse cell types into the immune system by showing that they can deploy an IFN-γ–induced restriction factor against bacteria in their cytosol (see the figure). The findings of Gaudet et al. also weaken a conceptual boundary established in the early 1990s, when immunologists divided the immune system into two modes, innate and adaptive. Innate immunity, it was proposed, kills pathogens directly. Individual granulocytes and macrophages of the innate immune system are not clonally distinct, so large numbers can be mobilized quickly, but they lack specificity and memory. Adaptive immunity depends on lymphocyte clones that proliferate upon encountering a specific antigen for which they display a receptor. Persistence of expanded clones with high-affinity receptors provides memory. This binary view accommodated some cross-talk: Dendritic cells present antigen to lymphocytes along with signals that prepare them to proliferate; lymphocytes recognizing antigen secrete IFN-γ to instruct macrophages to increase their killing capacity and make antibodies that frustrate pathogens' attacks or mark them for destruction by phagocytes or complement. However, recent discoveries highlight the importance of innate lymphocytes that lack antigen receptors. Such cells can make IFN-γ, including at the command of granulocytes ([ 10 ][9]), bypassing adaptive cells. Lymphocytes that have antigen receptors can kill bacteria ([ 11 ][10]) without relying on innate cells. Persistent epigenetic changes can endow innate lymphocytes and macrophages with memory ([ 12 ][11]). ![Figure][12] Dissolving bacteria Upon detection of a bacterial infection, interferon-γ (IFN-γ)-induced expression of apolipoprotein L3 (APOL3) in epithelial and endothelial cells, and fibroblasts, protects these cells from invading bacteria. GRAPHIC: KELLIE HOLOSKI/ SCIENCE The study of Gaudet et al. adds support to the following points of view. Every type of non–disease-causing cell resident in a human can potentially be a part of the immune system. Lymphocytes and macrophages can work in both innate and adaptive modes. Biochemically, cells kill other cells or themselves in a limited number of convergently evolved but divergently activated ways, including by making holes in membranes (shooting); oxidizing cellular constituents (burning); and (in)activating multiple enzymes and channels (poisoning). The immune system's challenge is to optimally deploy its effectors against faster-evolving foes, minimize collateral damage, and help to repair it. APOL3 alone did not disrupt the inner membrane of Gram-negative bacteria. Other IFN-γ–induced factors made the bacteria susceptible to APOL3, including guanylatebinding protein 1 (GBP1) ([ 4 ][3]). This guanosine triphosphate (GTP)–hydrolyzing enzyme disrupted the outer bacterial membrane, allowing APOL3 access to the inner membrane. It will be interesting to examine whether apolipoproteins and GBPs cooperate to kill mycobacteria, whose maintenance of an outer lipid layer is analogous to that of Gram-negative bacteria. No mutations in APOL3 have been associated with an immunodeficiency, so it is unknown if APOL3 makes a nonredundant contribution to immunity. Loss-of-function mutations in human genes involved in production of, or response to, IFN-γ chiefly lead to increased susceptibility to mycobacterial infections, but also to increased susceptibility to Salmonella ([ 13 ][13]), an organism lysed by APOL3 ([ 4 ][3]). Perhaps such susceptibilities reflect, at least in part, a failure to induce APOL3. Administration of IFN-γ reduces the incidence of infections in people with chronic granulomatous disease ([ 14 ][14]), without correcting their leukocytes' defect in production of reactive oxygen species. Perhaps the mechanisms of protection include induction of apolipoproteins and GBPs. Future research should address which cells express APOL3 and the other IFN-γ–induced, intracellular apolipoproteins in vivo, and what functions are served by each. Perhaps one of them helps kill intracellular Trypanosoma cruzi , the agent of Chagas disease, given that circulating apolipoprotein L1 (APOL1) kills extracellular Trypanosoma brucei , which causes sleeping sickness ([ 15 ][15]). Some of the bacteria that are susceptible to destruction by APOL3 plus GBP1 are nonetheless pathogenic. Perhaps they express counter-mechanisms, as is the case with T. brucei that resist lysis by APOL1 ([ 15 ][15]). It will be interesting to determine how and to what extent GBP1 and APOL3 discriminate between bacterial membranes and the host's own bacteria-like mitochondrial membranes. Damage to mitochondria can increase their release of reactive oxygen species, which could further contribute to IFN-γ–induced antibacterial immunity. Interferons were identified as proteins that induce an antiviral state in cells considered to lie outside the immune system. Now, IFNγ from innate and adaptive lymphocytes can instruct such cells to express proteins that kill bacteria within them. This reminds us not to let the affiliation given to cell types constrain our understanding of their functions. Just as cells of the conventional immune system contribute to homeostasis in every organ, so can other cells in every organ contribute to immunity. 1. [↵][16]1. C. F. Nathan, 2. H. W. Murray, 3. M. E. Wiebe, 4. B. Y. Rubin , J. Exp. Med. 158, 670 (1983). [OpenUrl][17][Abstract/FREE Full Text][18] 2. 1. C. F. Nathan et al ., N. Engl. J. Med. 315, 6 (1986). [OpenUrl][19][CrossRef][20][PubMed][21][Web of Science][22] 3. [↵][23]1. G. Karupiah et al ., Science 261, 1445 (1993). [OpenUrl][24][Abstract/FREE Full Text][25] 4. [↵][26]1. R. Gaudet et al ., Science 273, eabf8113 (2021). [OpenUrl][27] 5. [↵][28]1. K. J. Tracey , Nature 420, 853 (2002). [OpenUrl][29][CrossRef][30][PubMed][31][Web of Science][32] 6. [↵][33]1. S.-Y. Zhang et al ., Curr. Opin. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334345
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Carl Nathan. Rethinking immunology[J]. Science,2021.
APA	Carl Nathan.(2021).Rethinking immunology.Science.
MLA	Carl Nathan."Rethinking immunology".Science (2021).