CeMM Principal Investigator
Our goal is to understand how immunity and metabolism are integrated at the organismal level. Adaptive lymphocytes of higher vertebrates play an essential role in immunity and perform extensive accessory functions that contribute to tissue homeostasis. Although the fundamental operative principles of immune cells are well characterized, many functional mechanisms still lack contextualization in physiological settings and therefore fail to yield novel concepts and therapeutic avenues. We are investigating how metabolic cues affect the differentiation and function of T cells. Our studies focus on the intestinal mucosa, where T cells are exposed to a myriad of microbial metabolites and dietary nutrients. We also want to understand how changes in organismal metabolism that occur as a consequence of gastrointestinal infections impact immune responses. Our group uses gnotobiotic husbandry, engineered bacterial strains, metabolomics and experimental infection to identify novel mechanisms contributing to the regulation of T cell function in physiological settings.
Coordination of host and microbial physiology at the intestinal mucosa
The mammalian gut harbors trillions of bacteria that extensively modify diet and host-derived molecules, generating a number of biologically active substances with direct nutritional value and signaling capabilities. Although the overall impact of microbial colonization on the host has been characterized, the effects of dynamic changes in bacterial metabolism on intestinal physiology and mucosal immunity are currently unknown. Microbial metabolism of dietary fibers and bile acids promotes the extrathymic differentiation of regulatory T cells, an anti-inflammatory cell type essential for the maintenance of immunological tolerance. Since the presence of both fibers and bile acids in the intestinal lumen is contingent on feeding, these findings suggest that microbial metabolites with immunoregulatory activity are produced in the fed state. To study how feeding-induced changes in microbial metabolism dynamically regulate host physiology at the intestinal mucosa, our group is using a curated list of bacterial molecules in a candidate- based approach, combined with unbiased, metabolomics-based profiling of bacterial metabolism in fed and fasted animals. By performing in vitro screens on immune cells and intestinal organoids, we hope to identify host targets that integrate microbial-derived cues produced in distinct absorptive states.
Intestinal immunity and metabolic adaptation during chronic helminthic infection
Infection is often accompanied by metabolic and behavioral alterations including fever, anhedonia and anorexia. Reduced feeding during infection decreases splenic lymphocyte numbers, suggesting the existence of metabolic states that better support immune function. Despite the well-characterized role of pleiotropic inflammatory cytokines in promoting sickness behavior, the effects of challenge-specific mediators on organismal physiology remain poorly characterized. Intestinal helminthic infections induce strong type 2 immune responses associated with a 10% increase in the resting metabolic rates of infected individuals in non-industrialized countries. The consequences of such metabolic shifts on immunity remain unknown. We are using transcriptional profiling and mouse genetic models to dissect the molecular pathways mediating organismal metabolic adaptation during helminthic infection with the goal of understanding how these changes impact the immunological balance at the intestinal mucosa.
Clarissa Campbell studied Biology with a minor in Genetics at the Federal University of Rio de Janeiro (UFRJ) and subsequently earned a master’s degree from the Oswaldo Cruz Foundation (FIOCRUZ) investigating how bacterial molecules exert immunomodulatory effects on mammalian cells via nuclear receptors, a topic she would continue to explore throughout her career. She joined the Tri-Institutional Immunology and Microbial Pathogenesis Program at Weill Cornell Medical College in New York as a graduate student where she specialized in mucosal immunology and regulatory T (Treg) cell biology. After obtaining her PhD, Clarissa remained under the mentorship of Dr. Alexander Rudensky at Memorial Sloan Kettering Cancer Center to continue her work on host- commensal interactions and pursue broader scientific questions bridging the fields of immunology and metabolism. Her research has characterized a circuit whereby microbial metabolites including short-chain fatty acids and secondary bile acids facilitate the differentiation of peripherally induced Treg cells, which in turn suppress immune responses to colonization and preserve a niche for a group of intestinal bacteria. More recently, she found that a bile acid-sensing nuclear receptor contributes to the cell-intrinsic responsiveness of effector T cells to fasting. Clarissa Campbell joined CeMM as a principal investigator in July 2021. Her lab is interested in investigating how changes in microbial and organismal metabolism contribute to regulate immune cell function.
Michaels AJ, Campbell C, Bou-Puerto R, Rudensk AY. Nuclear receptor LXRβ controls fitness and functionality of activated T cells. J Exp Med 2021 Apr 5;218(4):e20201311. (abstract)
Campbell C, Marchildon F, Michaels AJ, Takemoto N, van der Veeken J, Schizas M, Pritykin Y, Leslie CS, Intlekofer AM, Cohen P, Rudensky AY. FXR mediates T cell-intrinsic responses to reduced feeding during infection. Proc Natl Acad Sci USA. 2020 Dec 29;117(52):33446-33454. (abstract)
Campbell C, McKenney PT, Konstantinovsky D, Isaeva OI, Schizas M, Verter J, Mai C, Jin W-B, Guo C-J, Violante S, Ramos RJ, Cross JR, Kadaveru K, Hambor J, Rudensky AY. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature. 2020 May;581(7809):475-479. (abstract)
Campbell C, Rudensky A. Roles of Regulatory T Cells in Tissue Pathophysiology and Metabolism. Cell Metabolism. 2020 Jan 7;31(1):18-25. (abstract)
Campbell C, Dikiy S, Bhattarai SK, Chinen T, Matheis F, Calafiore M, Hoyos B, Hanash A, Mucida D, Bucci V, Rudensky AY. Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance. Immunity. 2018 Jun 19;48(6):1245-1257.e9. (abstract)
Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013 Dec 19;504(7480):451-5. (abstract)
Jenq RR, Ubeda C, Taur Y, Campbell C, Khanin R, Dudakov JA, Liu C, West ML, Singer NV, Equinda MJ, Gobourne A, Lipuma L, Young LF, Smith OM, Ghosh A, Hanash AM, Goldberg JD, Aoyama K, Blazar BR, Eric G Pamer, Marcel R M van den Brink. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. The Journal of Experimental Medicine. 2012 May 7;209(5):903-11 (abstract)
Araújo CV, Campbell C, Gonçalves-de-Albuquerque CF, Molinaro R, Cody MJ, Yost CC, Bozza PT, Zimmerman GA, Weyrich AS, Castro-Faria-Neto HC, Silva AR. A PPARγ agonist enhances bacterial clearance through neutrophil extracellular trap formation and improves survival in sepsis. Shock. 2016 Apr;45(4):393-403. (abstract)