Dan Corral

National Institutes of Health

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Yasmine Belkaid

National Institute of Allergy and Infectious Diseases

Denis Hudrisier

Institut de Pharmacologie et de Biologie Structurale

Liang Chi

National Institute of Allergy and Infectious Diseases

Olivier Neyrolles

Université de Toulouse

Verena M. Link

National Institute of Allergy and Infectious Diseases

Daniel Yong

National Institute of Allergy and Infectious Diseases

Nicolas Bouladoux

National Institutes of Health

Yannick Poquet

Institut de Pharmacologie et de Biologie Structurale

Christel Vérollet

Institut de Pharmacologie et de Biologie Structurale

Geanncarlo Lugo‐Villarino

Université de Toulouse

Cooperative Institutions

Centre National de la Recherche Scientifique

National Institutes of Health

Université Toulouse III - Paul Sabatier

Université de Toulouse

Institut de Pharmacologie et de Biologie Structurale

National Institute of Allergy and Infectious Diseases

Inserm

Government of the United States of America

Consejo Nacional de Investigaciones Científicas y Técnicas

Cornell University

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Homeostatic intestinal immunity is dominated by microbiota-independent cytotoxic Th1 cells

The Journal of Immunology (2023)

Eduardo Ansaldo Gine Taryn McFadden Daniel Yong Nicolas Bouladoux Verena M. Link

Abstract Barrier tissues such as the skin and gut form the first line of defense against pathogens and establish an immune dialogue with the resident microbiota. To that end, they harbor immune populations geared towards barrier function, tolerance, and repair. Of particular interest are the large numbers of T cells. Some are specific towards commensal microbes or recognize previously encountered pathogens. However, the origin, antigen specificity, and function of most barrier tissue-resident T cells remains elusive. We have identified a dominant CD4 T cell population in the small intestine lamina propria characterized by the expression of T-bet. Surprisingly, this population is present in both germ-free and conventionally reared (SPF) mice at homeostasis, and accounts for almost half of T cells at this site. Bulk and single-cell transcriptome analysis revealed that this population has cytotoxic potential. Furthermore, single-cell TCR sequencing showed parallel T cell repertoires in germ-free and SPF mice, suggesting shared antigen specificity. To explore the ontogeny of this population, we have identified clonally expanded TCRs and are generating low frequency retrogenic mice. Additionally, we have generated several T cell hybridomas from small intestine Th1 cells. Interestingly, preliminary results suggest that small intestinal Th1 TCRs exhibit some degree of self-reactivity, which may determine their development and differentiation in a foreign antigen-independent manner. Collectively, these studies will shed light on the function of a dominant intestinal T cell population and reveal novel insights into homeostatic tissue immune networks. This research was supported by the Intramural Research Program of NIAID, NIH.

Lamina propria

10.4049/jimmunol.210.supp.218.18

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Androgen signaling shapes the sexual differences of skin immunity by regulating ILC2 and dendritic cells

The Journal of Immunology (2023)

Liang Chi Inta Gribonika Dan Corral Julia Gschwend Seong‐Ji Han

Abstract The skin immune system mediates the skin health status, but the sex differences of the skin immune system are still unclear. This study aims to investigate sex differences in the skin immune system and decipher the underlying regulatory factors. We found that female mice have a higher magnitude of adaptive immune responses during commensal bacteria association and pathogen infection. Correspondingly, females have a higher level of skin dendritic cells (DCs), which play a fundamental role in commensal-induced adaptive immune responses. These sex differences were regulated by male sex hormones, that castration of males normalized the sex differences in the level of skin immune cells as well as the adaptive immune responses to bacteria. However, our scRNA-seq data reveals that androgen receptor is not expressed in DCs, but highly expressed in skin ILC2. Females have a significantly higher level of ILC2 than males and ILC2 from females also have a more activating gene expression signature than ILC2 from males. Females also have a significantly higher level of ILC2-produced IL-13 and GM-CSF than male mice. In addition, our data reveal that IL-13 and GM-CSF play a critical role to maintain the level of skin DCs, that IL-13/GM-CSF deficient mice have a remarkable decrease of skin DCs, and the sex differences of DCs are also largely impaired. Therefore, based on these findings, we suggest that androgen signaling negatively regulates the level of skin ILC2 and DCs, thereby shaping sex-specific skin immunity to commensals, pathogens, and/or other stimuli. Collectively our work proposes a mechanism for the heighten immunity observed in female and have important implication for our understanding of tissue immunity in the context of infection and cancer.

10.4049/jimmunol.210.supp.160.02

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Mammary Intra-Epithelial Lymphocytes Promote Lactogenesis and Offspring Fitness

Dan Corral Andrea Pichler Daniel Yong Katharine Yang Verena M. Link

Breastfeeding is an obligatory requirement of mammalian survival. This process is associated with the adaptation of maternal physiology including transformation of the mammary gland into a milk-secreting organ. How maternal immunity contributes to mammary gland remodeling and function remains largely unknown. Here, we show that maternal adaptive immunity plays a critical role in shaping lactogenesis. Specifically, physiological adaptation during pregnancy is associated with thymic involution and paradoxical enrichment in intraepithelial lymphocyte (IEL) precursors that no longer migrate to the gut, but instead preferentially accumulate within the mammary gland. Within this compartment, IEL precursors differentiate into T-bet-expressing unconventional CD8aa lymphocytes with a cytotoxic signature which accumulate within the mammary epithelium in an IL-15-dependent manner. Mammary IEL control milk production by favoring differentiation of both contractile and milk-secreting cells, thereby promoting offspring fitness. Altogether, this work uncovers a previously unappreciated contribution of the maternal adaptive immune system in organismal remodeling during pregnancy.

10.2139/ssrn.4712299

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Metabolic regulation of ILC2 differentiation into ILC1-like cells during Mycobacterium tuberculosis infection

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Dan Corral Alison Charton Maria Z. Krauss Eve Blanquart Florence Levillain

Abstract Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis, protect against pathogens at mucosal surfaces and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues within tissues remains to be fully understood. Here, we show that Mycobacterium tuberculosis infection alters the phenotype and function of immature lung ILC2 toward a protective interferon-γ-producing ILC1-like population. This differentiation is controlled by type 1 cytokines and is associated with a glycolytic program involving the transcription factor HIF1α. Collectively, our data reveal how tissue-resident ILCs adapt to type 1 inflammation toward a pathogen tailored immune response.

Innate lymphoid cell

10.1101/2021.01.19.427257

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Host-Derived Lipids from Tuberculous Pleurisy Impair Macrophage Microbicidal-Associated Metabolic Activity

Cell Reports (2020)

José Luis Marín Franco Melanie Genoula Dan Corral Gabriel Duette Malena Ferreyra

Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host, yet the responsible mechanisms remain elusive. Macrophage activation toward the microbicidal (M1) program depends on the HIF-1α-mediated metabolic shift from oxidative phosphorylation (OXPHOS) toward glycolysis. Here, we ask whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We expose M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PEs) and find lower glycolytic activity, accompanied by elevated levels of OXPHOS and bacillary load, compared to controls. The eicosanoid fraction of TB-PE drives these metabolic alterations. HIF-1α stabilization reverts the effect of TB-PE by restoring M1 metabolism. Furthermore, Mtb-infected mice with stabilized HIF-1α display lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages (AMs). Collectively, we demonstrate that lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection.

Metabolic pathway

10.1016/j.celrep.2020.108547

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Host-Derived Lipids from Tuberculous Pleurisy Impair Macrophage Microbicidal-Associated Metabolic Activity

SSRN Electronic Journal (2020)

José Luis Marín Franco Melanie Genoula Dan Corral Gabriel Duette Malena Ferreyra

Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host. Yet, the responsible mechanisms remain elusive. Macrophage activation towards the microbicidal (M1) program depends on the HIF-1α-mediated metabolic shift from oxidative phosphorylation towards glycolysis. Here, we asked whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We exposed M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PE), and found lower glycolytic activity, accompanied by elevated levels of oxidative phosphorylation and bacillary load, compared to controls. The host-derived lipid fraction of TB-PE drove these metabolic alterations. HIF-1α stabilization reverted the effect of TB-PE by restoring M1 metabolism. As a proof-of-concept, Mtb-infected mice with stabilized HIF-1α displayed lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages. Collectively, we demonstrate that host-derived lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection.

Pleurisy

10.2139/ssrn.3553403

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Metabolic Control of Type 2 Innate Lymphoid Cells Plasticity Toward Protective Type 1-Like Cells During <i>Mycobacterium Tuberculosis</i> Infection

SSRN Electronic Journal (2021)

Dan Corral Alison Charton Maria Z. Krauss Eve Blanquart Florence Levillain

Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis and protect against pathogens at mucosal surfaces and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues in their tissue of residence remains to be fully understood. Here we show that Mycobacterium tuberculosis infection alters the biology of lung ILCs and, in particular, induces the emergence of a non-classical, protective, interferon-γ-producing ILC1-like population. Adoptive transfer, fate-mapping and in vitro differentiation experiments revealed that ILC1-like cells originate from immature ILC2 rather than from mature ILC2. This plasticity is controlled by type 1 cytokines and a glycolytic program involving the transcription factor HIF1α. Collectively, our data reveal how tissue-resident ILCs adapt to their inflammatory and metabolic environment to undergo phenotypic and functional changes toward a pathogen-adapted immune response.

Innate lymphoid cell

10.2139/ssrn.3787899

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Host-derived lipids from tuberculous pleurisy impair macrophage microbicidal-associated metabolic activity

bioRxiv (Cold Spring Harbor Laboratory) (2020)

José Luis Marín Franco Melanie Genoula Dan Corral Gabriel Duette Malena Ferreyra

SUMMARY Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host. Yet, the responsible mechanisms remain elusive. Macrophage activation towards the microbicidal (M1) program depends on the HIF-1 α-mediated metabolic shift from oxidative phosphorylation towards glycolysis. Here, we asked whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We exposed M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PE), and found lower glycolytic activity, accompanied by elevated levels of oxidative phosphorylation and bacillary load, compared to controls. The host-derived lipid fraction of TB-PE drove these metabolic alterations. HIF-1α stabilization reverted the effect of TB-PE by restoring M1 metabolism. As a proof-of-concept, Mtb-infected mice with stabilized HIF-1α displayed lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages. Collectively, we demonstrate that host-derived lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection.

Metabolic pathway

10.1101/2020.03.23.001818

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Microbiota configuration determines nutritional immune optimization

Proceedings of the National Academy of Sciences (2023)

Seong‐Ji Han Apollo Stacy Dan Corral Verena M. Link Mirian Krystel De Siqueira

Mild or transient dietary restriction (DR) improves many aspects of health and aging. Emerging evidence from us and others has demonstrated that DR also optimizes the development and quality of immune responses. However, the factors and mechanisms involved remain to be elucidated. Here, we propose that DR-induced optimization of immunological memory requires a complex cascade of events involving memory T cells, the intestinal microbiota, and myeloid cells. Our findings suggest that DR enhances the ability of memory T cells to recruit and activate myeloid cells in the context of a secondary infection. Concomitantly, DR promotes the expansion of commensal Bifidobacteria within the large intestine, which produce the short-chain fatty acid acetate. Acetate conditioning of the myeloid compartment during DR enhances the capacity of these cells to kill pathogens. Enhanced host protection during DR is compromised when Bifidobacteria expansion is prevented, indicating that microbiota configuration and function play an important role in determining immune responsiveness to this dietary intervention. Altogether, our study supports the idea that DR induces both memory T cells and the gut microbiota to produce distinct factors that converge on myeloid cells to promote optimal pathogen control. These findings suggest that nutritional cues can promote adaptation and co-operation between multiple immune cells and the gut microbiota, which synergize to optimize immunity and protect the collective metaorganism.

10.1073/pnas.2304905120

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Skin immunity during pregnancy

The Journal of Immunology (2023)

Lillian Sun Dan Corral Liang Chi Michel Enamorado Nicolas Bouladoux

Abstract Pregnancy presents a challenging immunological dilemma. The maternal immune system must tolerate fetal antigens, which implies pregnancy may induce specific mechanisms of immunoregulation. Yet within this regulatory milieu, protection against pathogens must be maintained. How does the maternal immune system navigate these opposing demands? Successfully navigating this immunological dilemma is essential for supporting the reproductive fitness of the organism, and generally, the survival of any mammalian species. Of particular importance in this context are barrier tissues, like the skin, which represent the primary portal of entry for pathogens. These barrier tissues are an especially important first line of defense during pregnancy, since adaptive immunity must be regulated to tolerate the fetal antigens which distribute throughout maternal tissues. However, little is known about how immunity in barrier tissues is altered during pregnancy. Our preliminary studies have identified an increase in ceramide levels in the skin during pregnancy. Ceramides have been shown to be critical mediators of skin barrier function, and may prevent pathogens from breaching the skin. Additionally, in the setting of S. aureus infection, pregnant skin demonstrated increased infiltration of innate immune cells, as well as an increase in type I immunity among adaptive cells. Together, these data suggest that the protective mechanisms of the skin are altered during pregnancy. Further insights in this area may elucidate an especially critical role for barrier tissue immunity in defending against infection during pregancy, and may eventually help guide improved clinical strategies to prevent and treat infections in pregnant mothers. Supported by Perelman School of Medicine's Medical Scientist Training Program and intramural research funding from NIAID.

10.4049/jimmunol.210.supp.61.21

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