{"id":51322,"date":"2024-12-12T11:00:38","date_gmt":"2024-12-12T19:00:38","guid":{"rendered":"https:\/\/www.salk.edu\/?post_type=disclosure&p=51322"},"modified":"2024-12-12T14:06:04","modified_gmt":"2024-12-12T22:06:04","slug":"your-immune-cells-are-what-they-eat","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/es\/news-release\/your-immune-cells-are-what-they-eat\/","title":{"rendered":"Tus c\u00e9lulas inmunitarias son lo que comen"},"content":{"rendered":"

LA JOLLA\u2014The decision between scrambled eggs or an apple for breakfast probably won\u2019t make or break your day. However, for your cells, a decision between similar microscopic nutrients could determine their entire identity. If and how nutrient preference impacts cell identity has been a longstanding mystery for scientists\u2014until a team of Salk Institute immunologists revealed a novel framework for the complicated relationship between nutrition and cell identity.\r\n<\/p>

\r\nThe answers came while the researchers were exploring different kinds of immune cells. The immune system relies on specialized \u201ceffector\u201d T cells to fight off pathogens, but in chronic infections like HIV or cancers, the perpetual activation of these cells can turn them into \u201cexhausted\u201d T cells unable to continue fighting. In the new study, Salk scientists discovered that a nutritional switch from acetate to citrate plays a key role in determining T cell fates, shifting them from active effector cells to exhausted cells. This finding highlights how metabolic changes influence T cell identity and opens avenues for interventions to sustain immune function.\r\n<\/p>\r\n

\"From<\/a>
From left: Susan Kaech, Shixin Ma, and Thomas Mann.\r\n
Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\r\n
\"From<\/a>
From left: Russell Jones and Michael Dahabieh.\r\n
Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Credit: Van Andel Institute<\/figcaption><\/figure>\r\n

\r\nThe discovery that different nutrients can change a cell\u2019s gene expression, function, and identity significantly advances scientists\u2019 understanding of the relationship between nutrition and cellular health throughout the body. It may also be possible to develop new therapies that target these nutrient-dependent mechanisms to help T cells stay active and energetically optimized against chronic diseases like cancer or HIV. \r\n<\/p>

\r\nLos hallazgos fueron publicados en Ciencia<\/a><\/em> on December 12, 2024.\r\n<\/p>

\r\n\u201cYou know the saying, \u2018You are what you eat?\u2019 Well, we uncovered a way in which this actually operates in cells,\u201d says Professor Susan Kaech<\/a>, senior author of the study and holder of the NOMIS Chair at Salk. \u201cThis is really exciting on two levels: on a fundamental level, our findings show that a cell\u2019s function can be directly linked to its nutrition; on a more specific level, this sheds new light on how T cells become dysfunctional or exhausted and what we could do to prevent that.\u201d\r\n<\/p>

\r\nMetabolism is a central cellular process that processes nutrients<\/em> into metabolites<\/em> y energy<\/em>. Nutrients provide the resources for all cellular activities, but they must first be broken down into smaller molecules called metabolites. Metabolites have many uses, including promoting epigenetic regulation<\/em>, a process that changes the shape of a cell\u2019s DNA to alter the accessibility of different genes. Which genes are expressed in a cell at any given time then determines the behavior and identity of the entire cell. \r\n<\/p>

\r\nThe team wondered: Could this change in metabolism be responsible for the epigenetic changes that turn effector T cells into exhausted T cells? Is there a link between nutrition and exhausted T cell differentiation?\r\nOne of the most important and common metabolites is acetyl-CoA, which both effector and exhausted T cells make\u2014but with one interesting difference. Exhausted T cells tend to make their acetyl-CoA using a protein called ACLY that uses citrate, rather than using a protein called ACSS2 that uses acetate.\r\n<\/p>\r\n

\r\nThe preferential activity of citrate-using-ACLY in exhausted T cells and acetate-using-ACSS2 in effector T cells piqued the team\u2019s curiosity, leading them to genetically investigate the production of these metabolic proteins in both T cell subtypes. They found that ACSS2 gene expression was most highly expressed in functional T cells, but was drastically reduced in exhausted T cells in both mouse and human tissue samples. In contrast, ACLY genes were expressed similarly in both effector and exhausted T cells\u2014with slightly greater expression in the exhausted cells. This suggested that T cells needed to express ACSS2 to maintain a functional state and that with exhaustion comes a greater reliance on ACLY.\r\n<\/p>

\r\nTo verify their findings, they went into the T cells and deleted ACLY and ACSS2 genes one at a time\u2014discovering that the loss of ACLY boosted anti-tumor T cell activity, while the loss of ACSS2 did the opposite and reduced T cell efficacy. Seeing these differences in expression of ACLY and ACSS2 then led to a line of questioning about whether the downstream acetyl-CoA derived from these proteins may be determining the formation of exhausted T cells.\r\n<\/p>\r\n

\"Two<\/a>
Two T cells whose nutritional choices have changed their identity. On the left, a blue T cell prefers acetate and is active, able to continue fighting. On the right, a red T cell prefers citrate and is exhausted, no longer able to fight effectively.\r\n
Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\r\n

\r\n\u201cWe were shocked and thrilled to find the types of nutrients our cells were using changed their genetic expression and identities, meaning we have a whole new nutrient-dependent process to target with therapeutics that better equip us to fight chronic illness,\u201d says Shixin Ma, first author of the study and postdoctoral researcher in Kaech\u2019s lab. \r\n<\/p>

\r\nExhausted T cells were bailing on ACSS2 and relying heavily on ACLY, forcing themselves to use more citrate and less acetate to create acetyl-CoA, despite equal availability of both nutrients. Upon closer inspection, the researchers noticed that two distinct pools of otherwise identical acetyl-CoA were piling up in different locations in the nucleus\u2014where the cell\u2019s DNA is stored\u2014based on whether it was derived from acetate via ACSS2 or from citrate via ACLY. Each nutrient-specific pile was then linked to unique histone acetyltransferases, which are proteins that reshape DNA and influence which genes are expressed to change cellular behavior and identity.\r\n<\/p>

\r\nIn a sort of domino effect, the original nutrient was ultimately determining T cell fate\u2014(1) the metabolic enzyme (ACSS2 or ACLY) determined the nutrient used, (2) the metabolic enzyme determined the location of acetyl-CoA, (3) the location of acetyl-CoA determined what gene-modifying histone acetyltransferases were activated, and (4) those histone acetyltransferases either maintained the effector T cell identity or encouraged the shift to exhausted T cell identity.\r\n<\/p>

\r\nThis novel link between nutrition and cell identity offers a new explanation for exhausted T cell identity and in turn offers a multitude of new targets for future therapeutics that could keep T cells turned \u201con\u201d longer. \r\n<\/p>

\r\n\u201cTruly, this is a radical concept that hasn\u2019t been seen before,\u201d says Kaech. \u201cWe are seeing clear consequences in cellular identity and function based on nutrient preferences by cells. The impact of these findings won\u2019t just be within immunotherapy and immunology\u2014every cell type in the body<\/em> uses these metabolic processes, so plenty of other discoveries and therapeutic innovations can come out of what we\u2019ve found.\u201d\r\n<\/p>

\r\nOther authors include Thomas Mann, Steven Zhao, Bryan McDonald, Yagmur Farsakoglu, Lizmarie Garcia-Rivera, Filipe Araujo Hoffmann, Shihao Xu, Victor Du, Dan Chen, Jesse Furgiuele, Michael LaPorta, and Emily Jacobs of Salk; Michael Dahabieh, Lisa DeCamp, Brandon Oswald, Ryan Sheldon, Abigail Ellis, and Russell Jones of the Van Andel Institute; Won-Suk Song and Cholsoon Jang of UC Irvine; H. Kay Chung of Salk and the University of North Carolina at Chapel Hill; Longwei Liu and Yingxiao Wang of the University of Southern California; and Peixiang He of UC San Diego.\r\n<\/p>

\r\nThe work was supported by the National Institutes of Health (R01 AI066232, R21 AI151986, R01 AI165722, R01 AA029124, EB R01 029122, GM R35 140929, K00CA222741, P30 CA01495, S10-OD023689, S10 OD034268, P30 AG068635, T32CA009370), Chapman Foundation and the Helmsley Charitable Trust, Paul G. Allen Family Foundation, Van Andel Institute, American Association for the Study of Liver Diseases Foundation, Edward Mallinckrodt Jr. Foundation, Cancer Research Institute, Damon Runyon Cancer Research Foundation, and a Salk Pioneer Fund Postdoctoral Scholar Award.\r\n<\/p>","protected":false},"featured_media":51892,"template":"","faculty":[311],"disease-research":[46,457,122,123],"class_list":["post-51322","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-susan-kaech","disease-research-cancer-biology","disease-research-hiv","disease-research-immune-system-biology","disease-research-metabolism-and-diabetes"],"acf":[],"yoast_head":"\nYour immune cells are what they eat - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/es\/news-release\/your-immune-cells-are-what-they-eat\/\" \/>\n<meta property=\"og:locale\" content=\"es_MX\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Your immune cells are what they eat - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014The decision between scrambled eggs or an apple for breakfast probably won\u2019t make or break your day. 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