From the Thymus to the Mucosa: A Three-Decade Journey Dan R. Littman This information is current as J Immunol 2017; 199:2183-2187; ; of September 26, 2021. doi: 10.4049/jimmunol.1790016 http://www.jimmunol.org/content/199/7/2183 Downloaded from References This article cites 20 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/199/7/2183.full#ref-list-1

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. From the Thymus to the Mucosa: A Three-Decade Journey Dan R. Littman t was a great privilege for me to serve on the American Association of Immunologists (AAI) Council and to be I President of the AAI during the 2015–16 cycle. I par- ticularly appreciate this opportunity to reminisce a bit about how my early interest in immunology led to the studies in which my laboratory is currently engaged. I titled my AAI presentation “From the Thymus to the Mucosa” because, during the past three decades, my group’s interests progressed from those around development of cells within the thymus to those related to how T cells differentiate in response to gut Downloaded from microbiota. My interest in science was sparked in my early years. Growing up as a child in Romania at the outset of the space age, I was most excited by the prospect of space exploration. Indeed, after my family emigrated to the United States, I entered Princeton University intent on studying aerospace http://www.jimmunol.org/ engineering. My engineering interest was short-lived, how- ever, as I discovered that I wanted a broader-based education, and I switched to majoring in biochemistry after reading some books, including Watson’s Molecular Biology of the Gene.My love of research was sparked by my experience after I joined the laboratory of Marc Kirschner, a new assistant professor who inspired me to spend day and night in a cold room studying the physical properties of polymerization of micro- by guest on September 26, 2021 tubules. That was my first hands-on exposure to science, and I remember spending all-nighters counting drops for viscosity assays of polymerizing microtubules. This laboratory experience firmed up my resolve to go into experimental science, but another event led me to immu- Dan R. Littman nology. There were no immunologists at Princeton University at that time (and there have been notably few in the following decades) and so Arnie Levine, a virologist at Princeton Uni- flammatory diseases. The question of self/nonself recognition versity, enlisted his friend Norman Klinman, then at the featured prominently in my choice of a laboratory in which to University of Pennsylvania, to organize a course on immu- carry out my research project after entering the M.D./Ph.D. nology. They proceeded to invite many of the top immu- program at Washington University in St. Louis. Ben Schwartz nologists in the world to give lectures. I was fortunate to sit in and Susan Cullen had recently joined the faculty after com- on the course and became very excited about problems pre- sented by the field of immunology. Big questions back then pleting their postdoctoral fellowships at the National Institutes were based around how diversity is generated and how self of Health, and I joined their joint laboratory as their first versus nonself recognition is achieved. Although we now have a graduate student. I decided to ask whether recognition of viral detailed mechanistic understanding of diversity, much still Ag and MHC was carried out by one or two receptors on remains to be learned about the regulation of autoreactivity, T lymphocytes. To do this, I incorporated MHC and viral despite major discoveries of central and peripheral tolerance envelope glycoproteins into lipid vesicles, to ask whether they mechanisms. We still have only a sketchy understanding of could stimulate MHC-restricted virus-specific T cells (1). This ap- why tolerance breaks down in various autoimmune or in- proach failed, of course, as we did not consider Ag processing

The Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medi- Abbreviations used in this article: AAI, American Association of Immunologists; iTreg, cine, New York University School of Medicine, New York, NY 10016; and The Howard induced Treg; MIA, maternal immune activation; NYU, New York University; poly Hughes Medical Institute, New York University School of Medicine, New York, NY 10016 (I:C), polyinosinic-polycytidylic acid; SAA, serum amyloid A; SFB, segmented filamentous bacteria; Treg, regulatory . Address correspondence and reprint requests to Dan R. Littman, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 430 East 29th Street, Ó Room 403, New York, NY 10016. E-mail address: [email protected] Copyright 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1790016 2184 PRESIDENT’S ADDRESS

1 at that early time, but I learned a great amount and concluded and in activated CD4 T cells cultured with a combination of that I wanted to next join the laboratory of at IL-6 and TGF-b, conditions that favor Th17 cell differenti- Columbia University, where I could take advantage of the ation (6). new tools becoming available as part of the molecular biology Two features stood out in our initial characterization of revolution. There, I developed gene transfer approaches and the RORgt-dependent Th17 cells (6): first, these cells were 1 screens for isolation of genes encoding cell surface molecules. most abundant among CD4 T cells in the small intestine, Because of my interest in T cell lineages and thymic devel- consistent with subsequent findings that they promote tissue opment, I focused on the cloning of the genes encoding hu- repair at mucosal surfaces; and, second, many of the RORgt- man CD8 and, subsequently, CD4 (2, 3). During that time, dependent Th17 cells required for the autoimmune model it became increasingly clear that the newly discovered HIV experimental autoimmune encephalomyelitis expressed not 1 specifically attacked CD4 T cells and that led me to an in- only IL-17A, but also the Th1 cytokine IFN-g. As discussed terest in what accounts for this tropism. Thus, when I started below, we now know that these mixed Th1/Th17 cells are my own laboratory in 1985 in the Department of Microbi- dependent on signaling through IL-23R, are critical in auto- ology and Immunology at the University of California, San immune disease, and are similarly present in humans. Ivo Francisco, my goal was to understand the functions of CD4 Ivanov then found that animals treated with antibiotics or and CD8 in T cell development and activation and the po- rendered germ-free had few, if any, Th17 cells. He soon tential role of CD4 in HIV entry. thereafter made the serendipitous observation that some of the

Although our early interest was in how the coreceptors CD4 C57BL/6 mice in our colony had few intestinal Th17 cells, Downloaded from and CD8 function, particularly how they interact with TCR, whereas others had many, and this was dependent on the MHC class II and class I, and the tyrosine kinase Lck, my vendors from whom the mice were purchased. When the laboratory’s long-standing goal has been to understand how animals were cohoused, they all acquired large proportions of immature double-positive thymocytes are specified to become Th17 cells. This led to a collaboration with Kenya Honda 1 CD4 MHC class II–restricted Th cells (or regulatory T cells that revealed that colonization with a single microbial species, 1 [Tregs]) or CD8 MHC class I–restricted cytotoxic cells. segmented filamentous bacteria (SFB), a Gram-positive spore- http://www.jimmunol.org/ This is a problem that remains unsolved, but it has led us in forming anaerobe, determined the number of Th17 cells (7). interesting directions. We focused on characterizing tran- After colonization of germ-free mice with SFB, there was 1 scriptional programs that distinguish the lineages, anticipating massive induction of IL-17 and IL-22 in CD4 T cells. This that this would allow us to work backward toward identify- was beneficial to mice, as it protected them from pathogenic ing distinctions in signaling pathways initiated by interaction bacteria like enteropathic Escherichia coli or Citrobacter with different types of MHC molecules. By focusing on Cd4 rodentium. However, induction of Th17 cells by SFB also gene regulation, we identified a lineage-specific silencer that is predisposed animals to autoimmunity, as shown in the

regulated epigenetically by Runx family transcription factors, microbiota-dependent K/BxN model of spontaneous arthritis, by guest on September 26, 2021 particularly Runx3 that solidifies commitment of CD8 line- in collaboration with Diane Mathis and Christophe Benoist age cells while conferring heritability of Cd4 silencing func- (8). This result led us to study fecal microbiota in rheumatoid tion (4). It was in the context of our search for transcription arthritis patients, and Jose Scher, a clinical fellow at NYU, factors that regulate thymocyte lineage specification that we found that new-onset rheumatoid arthritis patients were much identified an important function for the nuclear receptor more likely than healthy controls to be colonized with the RORgt in lymphoid cells shortly after our laboratory relo- Gram-negative bacterium Prevotella copri (9). However, it is cated to the Skirball Institute at New York University (NYU) not yet known whether this bacterium has a causal role in (5). disease, nor is it understood how Th17 cells induced in the Although the discovery of a RORgt function in the thymus gut mucosa can contribute to systemic autoimmunity. This is did not provide insight into the lineage problem, it served as a a central question that is the focus of our current work. critical pivot toward our subsequent studies of the intestinal To elucidate the mechanism of SFB-induced autoimmunity, mucosa and, in turn, of the role of the in we initially investigated the specificity of the SFB-induced immune responses. Our early characterization of RORgt Th17 cells. Benny Yang showed that almost all of these function showed its importance for survival of double-positive Th17 cells have receptors specific for SFB-encoded Ags (10). In thymocytes, preventing death by neglect and giving the cells contrast, when we transplanted one of the immunogenic SFB an opportunity to undergo positive selection (5). Moreover, it genes into Th1-inducing Listeria monocytogenes, there was a led us to identify its requirement for the development of a Th1 response specific for the SFB Ag upon colonization with class of innate lymphoid cells, the lymphoid tissue inducer the modified Listeria. This indicated that it is the nature of the cells required for lymphoid organogenesis, including forma- bacterium, potentially the niche that they establish or the type tion of intestinal Peyer’s patches and tertiary lymphoid or- of signal that they transmit to APCs in their microenviron- gans. Shortly thereafter, using a mouse strain in which GFP ment, that determines whether the APCs will direct T cells reports on RORgt expression, Ivo Ivanov, a postdoctoral toward the Th17 or Th1 fate. In studies that nicely com- fellow, found lamina propria T cells that expressed relatively plemented our work on Th17 cells, Kenya Honda found that low levels of the transcription factor. Coincidentally, Dan a collection of clostridial species can induce Tregs and, thus, Cua’s group at DNAX found RORgt to be upregulated, confer some of the protective properties of Tregs in autoim- along with IL-17A, when activated T cells were treated with mune diseases or in allergies (11). In our laboratory, Mo Xu IL-23. Th17 cells had just been described and, in collabora- showed that Helicobacter hepaticus, which colonizes the large tion with the DNAX scientists, we showed that IL-17A is intestine, also induces Tregs that are specific for bacterial expressed in a RORgt-dependent manner in intestinal T cells Ag (see below). These findings raise the questions of how The Journal of Immunology 2185

1 different CD4 T cell programs are differentially induced by theterminalileum,anditwasonlyinthispartofthein- the diverse noninvasive intestinal bacteria and how induction testine that there were changes in gene expression. The most of effector cells in the draining lymph nodes contributes to highly upregulated genes were those encoding serum amy- systemic inflammatory diseases, such as arthritis. loid A (SAA) 1 and 2, which are secreted molecules known To investigate how the different types of T cells are induced as acute-phase reactants. Expression of these genes occurs by luminal microbes, we developed tools to study Ag speci- within 2–3 d following colonization with SFB and requires ficity, including mice with transgenic TCRs specific for Ags a cytokine signaling relay in the small intestinal lamina encoded by SFB or H. hepaticus and MHC class II tetramers propria. Thus, IL-23, produced by monocyte-derived cells, conjugated with bacterial peptides recognized by the T cells. activates group 3 innate lymphoid cells and induces their H. hepaticus had been shown by Fiona Powrie’s laboratory to production of IL-22, which binds to receptor on epithelial induce an inflammatory response, marked by cells with mixed cells to activate STAT3 phosphorylation–mediated tran- Th1 and Th17 properties, in mice deficient for IL-10 (12). By scription of Saa1/2. In the meantime, APCs drain to the studying H. hepaticus Ag-specific responses, Mo Xu demon- mesenteric lymph nodes, where they activate SFB-specific strated the induction of Tregs under noninflammatory (IL- naive T cells and direct their differentiation toward the 1 1 10–sufficient) conditions. In mice colonized with both SFB RORgt Th17 program. We found these RORgt T cells and H. hepaticus, transplanted TCR-transgenic T cells rec- distributed throughout the intestine and also in distal lymph 1 ognizing SFB differentiated into RORgt Th17 cells, whereas nodes and spleen, but they selectively produced IL-17A in 1 the T cells specific for H. hepaticus were largely RORgt theileum,inresponsetoasignalthatismediated,atleastin Downloaded from 1 Foxp3 induced Tregs. In contrast, when the T cells were part, by SAAs. Therefore, we have proposed a two-step introduced into colonized mice that had been treated with Ab process for activation of Th17 cell effector function in re- against IL-10R, SFB- and H. hepaticus–specific T cells became sponse to SFB (18). There is initial specification of the 1 RORgt , but only the latter were highly pathogenic Th17 program, marked by RORgt expression, in the draining cells that mediated colitis. These cells produced both IL-17A lymph node, and subsequent induction in target tissues of and IFN-g and had a very different profile of gene expression the effector functions by SAAs and other natural adjuvant- http://www.jimmunol.org/ than the SFB-specific Th17 cells. Studies from multiple lab- like molecules that have yet to be characterized. This raises oratories demonstrated that the “pathogenic Th17” cell pro- the possibility that weak self-antigen agonists may induce file of gene expression is dependent on IL-23R signaling in inflammatory cytokine production by SFB-specific T cells in T cells (13–15). Moreover, Stockinger’s group performed tissues in which local SAA levels are high. We have mount- fate-mapping studies showing that, in autoimmune disease ing evidence that SAAs may have such functions. For ex- 1 1 1 models, there are RORgt - and IL-23R–dependent IFNg ample, when activated CD4 T cells were exposed to IL-6, cells derived from IL-17A–expressing T cells (13). Such cells there was very little IL-17A and IL-17F production. However,

have properties that are similar to those described by Sallusto when recombinant SAA1 was included, there was marked by guest on September 26, 2021 1 1 (16) for CXCR3 CCR6 Th1* cells in humans. Casanova upregulation of IL-17 cytokines. This effect of SAAs was also and colleagues characterized individuals with immunodefi- observed under typical in vitro Th17-differentiation condi- ciency who had homozygous mutations in the gene encoding tions, with IL-6 and TGF-b, and with IL-6, IL-1b,andIL-23, RORg/gt and phenotypes very similar to those described in which are thought to induce “pathogenic” Th17 cells. We mutant mice. Remarkably, these individuals had reduced additionally observed a much milder disease course in the ex- Th17 and Th1* cells and were particularly susceptible to perimental autoimmune encephalomyelitis model in mice de- mycobacteria, because immunization with bacillus Calmette– ficient for SAA1 and SAA2 (J.Y. Lee and D.R. Littman, Gue´rin resulted in uncontrolled disseminated disease (17). unpublished observations). We therefore propose that SAAs These findings led us to propose that distinct commensal and other endogenous adjuvants trigger autoimmune inflam- 1 microbes induce nonpathogenic Th17 cells that protect bar- mation mediated by RORgt T cells whose differentiation rier surfaces (as SFB does) and potentially pathogenic Th1* requires appropriate intestinal microbiota (Fig. 1). cells (as induced by Candida albicans and by H. hepaticus). This two-step process for activation of Th17 cell functions Differentiation of the latter is promoted by IL-23 but is re- may also be important following innate antiviral responses, strained by induced Tregs (iTregs) and IL-10, which may be resulting in protective or pathogenic outcomes. An example induced by the same bacteria. The ability of bacteria to induce of the latter was uncovered in our studies of a mouse model of iTregs and pathogenic Th17 cells may be key to establish- neuropathology associated with an autism-like syndrome. ment of commensalism and, indeed, we have evidence that This model, named the maternal immune activation (MIA) 1 H. hepaticus–specific RORgt Tregs are essential to prevent model, was developed over the last several decades in the wake expansion of pathogenic Th17 cells that can mediate spon- of retrospective studies that reported an increased likelihood taneous colitis (M. Xu, M. Pokrovskii, and D.R. Littman, of autism in children born to mothers who had various in- unpublished observations). These findings highlight a major fections during early pregnancy. For this model, either a virus gap in our understanding as to how commensal microbiota or polyinosinic-polycytidylic acid [poly(I:C)], which activates signals direct T cells down different paths of differentiation. TLR3, is administered to the mother at day 12.5 of gestation. We have begun to investigate how different microbes direct This results in morphological changes in the CNS of the distinct programs of T cell differentiation. Our first efforts offspring and in behavioral abnormalities that last through were to study how SFB induces Th17 cells (18). We first adult life. The late Paul Patterson, who championed this examined changes in gene expression in intestinal epithelium model, found that the phenotype in the offspring required along the length of the gut following colonization with the intact IL-6 production in the mother (19). A colleague bacterium. SFB preferentially associates with epithelium in working at the Simons Foundation for Autism Research 2186 PRESIDENT’S ADDRESS

were treated with neutralizing anti–IL-17A Ab (20). Jun also performed in situ hybridization for expression of IL-17R in the fetal brain and found it in cells of the developing cortex. Remarkably, its expression was upregulated following MIA induction, consistent with the known positive feedback of IL-17R signaling. Moreover, there was a stereotyped defect in the morphology of the developing fetal cortex observed as early as embryonic day 14.5 and persisting into adult life. This was also eliminated with anti–IL-17A or if the mother was deficient in RORgt. The behavioral and morphological phenotypes were reproduced in the offspring in the absence ofMIAifIL-17Awasinjectedthroughtheuterinewallinto the fetal brain ventricles at embryonic day 14.5. These phenotypes were not observed if the fetus was deficient in IL- 17RA or if IL-6 was injected instead of IL-17A. Based on these results, we propose that inflammation that results in Th17 cell differentiation and IL-17A production in the

FIGURE 1. Proposed two-step mechanism for induction of Th17 cell mother, during a critical stage of gestation, can result in fetal Downloaded from effector functions. In the first step, Ag-specific naive T cells in the draining brain developmental abnormalities and in behavioral defects lymph nodes are primed by microbial Ag and receive microbe-specific in the offspring (20). But the production of the cytokine is polarizing signals that induce RORgt and other genes that define the dependent on a priming signal (signal 1), which could be the Th17-differentiation program. These T cells then migrate to diverse lym- microbiota, followed by an upsurge in IL-17 only after ex- phoid and nonlymphoid tissues (in the latter they may become tissue- posure to signal 2, mediated by infection with a pathogenic resident T cells), where they can receive innate adjuvant-like signals that microbe. We do not yet understand why IL-17R is expressed http://www.jimmunol.org/ activate expression of effector cytokines. SFB induces a “homeostatic” program of Th17 cell gene expression that, in the presence of local SAA1 in the brain, whether it contributes to normal development and SAA2, results in production of IL-17A, IL-17F, and IL-22. Patho- of the CNS, or whether it is also present in similar types of bionts, such as H. hepaticus, polarize microbe-specific CD41 T cells to- cells, which we have not yet fully identified, in humans. The ward a “pathogenic” Th17 cell program, with additional expression of implication of these results is that there may be a subset of GM-CSF (product of Csf2) and IFN-g. These Th17 cells are typically mothers who harbor a microbiota prone to elevating tissue H. hepaticus restrained from expanding through the activity of –specific Th17 cell numbers, which renders them more susceptible to Tregs that produce IL-10. The cellular and molecular details about how the different bacteria induce homeostatic versus pathogenic Th17 cells or having high levels of IL-17A.It may thus be possible to reduce iTregs remain to be elucidated. the incidence of disorders by prescreening by guest on September 26, 2021 women before or during pregnancy and intervening to reduce their circulating IL-17A. brought this article to my attention, and I was fortunate that In closing, I wish to reiterate that the microbiota can a new postdoctoral fellow, Jun Huh, expressed interest in the have positive and negative influences on our health. There is problem and decided to take it on as a side project. Although mounting evidence that it regulates susceptibility to autoim- this was a tangential direction for our laboratory, we suc- mune disease and that it may even influence development of ceeded in obtaining a pilot grant from the Simons Foun- the CNS. It is also likely that the microbiota can contribute to dation to study the pathway involved in the MIA phenotype. tumor progression and HIV pathogenesis. But, of course, the We had only recently learned that IL-6 was involved in the microbiota coevolved with us to provide mostly beneficial induction of RORgt and Th17 cells and, hence, hypothe- functions. Our goal is to harness such functions for use in sized that downstream Th17 cells might be involved in the improving barrier defenses, developing better vaccines, and autism spectrum disorder–like phenotype in the offspring. perhaps improving checkpoint immunotherapy, because there Jun confirmed that there was very rapid upregulation of clearly is a relationship between microbiota and efficiency of serum IL-6 after poly(I:C) challenge of the pregnant mice. CTLA-4 and PD-1 blockade. This was accompanied by a subsequent rise in serum IL-17A, and its level was sustained longer than that of IL-6. We bred conditional Rorc mutant mice with CD4-cre mice to spe- cifically knock out RORgtexpressioninTCRab T cells. As Disclosures expected, there was no elevation in IL-17A following injec- The author has no financial conflicts of interest. tion of poly(I:C) in the mutant pregnant dams. Jun (now at the University of Massachusetts Medical Center) then col- laborated with his wife, Gloria Choi, a superb neuroscientist References who is now at the Massachusetts Institute of Technology, 1. Littman, D. R., S. E. Cullen, and B. D. Schwartz. 1979. Insertion of Ia and H-2 and with our NYU colleague Charles Hoeffer to study be- alloantigens into model membranes. Proc. Natl. Acad. Sci. USA 76: 902–906. haviors in the offspring. They performed assays for social 2. Littman, D. R., Y. Thomas, P. J. Maddon, L. Chess, and R. Axel. 1985. The isolation and sequence of the gene encoding T8: a molecule defining functional interaction, communication, and repetitive behaviors. 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