\n\t\t\t\t\t\t\t\t\t\tBYLINE: Mario Aguilera\t\t\t\t\t\t\t\t\t\t<\/p>\n
Newswise \u2014 T cells are crucial components of our immune system, serving as critical protectors against infection and disease.<\/p>\n
But there are limits to their defensive capabilities. T cells are not inexhaustible protectors. Often, when T cells have engaged in killing tumor cells, they burn out and lapse into a dysfunctional state known as T cell exhaustion. Rebounding from exhaustion \u2014 or avoiding it altogether \u2014 would greatly aid their disease-fighting success. Today, rescuing T cells from burnout and getting them back into cancer-fighting shape is a major focus of cancer immunotherapy efforts.<\/p>\n
New research published in the journal Cell and led by Professor Ananda Goldrath\u2019s lab in the University of California San Diego School of Biological Sciences has uncovered an unexpected factor in our current understanding of T cell exhaustion.<\/p>\n
Protein homeostasis, or \u201cproteostasis,\u201d is a network of cellular processes that orchestrates the proper construction, movement and destruction of proteins in cells. One component of this network features a type of recycling function within cells. Healthy cells continuously dismantle old and damaged proteins to preserve energy and reuse building blocks to make new proteins.<\/p>\n
Led by Postdoctoral Fellow Nicole Scharping in Goldrath\u2019s Lab and including scientists from La Jolla Institute for Immunology and University of Arkansas for Medical Science, the study, featured on the cover of Cell, uncovered an impaired protein recycling function as the surprise culprit in T cell exhaustion.<\/p>\n
\u201cWe found that exhausted T cells\u2019 recycling programs are falling apart, leading to damaged and misfolded proteins that pile up with nowhere to go,\u201d said Scharping. But the research also uncovered a way to reverse the accumulation of misfolded proteins by fixing the broken recycling function and restoring normal proteostasis. Scharping said the issue can be resolved with a \u201ctag and sort\u201d fix. A family of enzymes called E3 ligases acts as labelers at a recycling facility, tagging worn-out proteins so the cell knows to break them down.<\/p>\n
\u201cIn exhausted T cells, many of these enzymes get switched off, and recycling grinds to a halt,\u201d said Scharping. \u201cWhen we restored specific E3 ligases, the buildup cleared, and the T cells regained their function and worked better at clearing tumors.\u201d<\/p>\n
Impaired protein processing is not unique to dysfunctional T cells, the researchers note. The findings hint that impaired protein recycling may tie together the biological process for diseases that are otherwise unrelated.<\/p>\n
\u201cWe think this loss of proteostasis resembles what occurs in neurons in other protein aggregate diseases such as Parkinson\u2019s and Alzheimer\u2019s,\u201d said Goldrath, a professor in the Department of Molecular Biology. \u201cRescuing these cells from exhaustion could improve the ability of T cells to respond to both chronic infection as well as tumors.\u201d<\/p>\n
The findings were aided by the use of mass spectrometry, an advanced analytical method that identifies and measures the mass of molecules, led by Professor Eric Bennett\u2019s lab at UC San Diego (Department of Cell and Developmental Biology) and Global Autoimmune Institute Assistant Professor Samuel Myers\u2019 lab at La Jolla Institute for Immunology. Mass spectrometry offered the ability to simultaneously examine thousands of proteins and suggest NEURL3, RNF149 and WSB1 as the E3 ligases responsible for rescuing T cell recycling functions.<\/p>\n
With these ligases back in place and the protein accumulation blockade cleared, the researchers found that they could boost the potency of cell therapy against cancer. While the new study was conducted in mice, the researchers indicate that similar strategies could be employed for immunotherapy treatments in human cancer.<\/p>\n
\u201cWe uncovered one of the mechanisms by which T cells lose their ability to fight cancer and now we have a target that we can use to design interventions to improve responses to immunotherapy as well as prevent chronic infection,\u201d said Goldrath.<\/p>\n
The full list of authors included: Nicole E. Scharping, Xuezhen Ge, Maria In\u00eas Matias, Fulin Jiang, Allison Cafferata, Maximilian Heeg, Alexander Monell, Giovanni Galletti, Kitty P. Cheung, Angelica Rock, Nick Thao, Sydnye L. Shuttleworth, Michael A. Bauer, Kennidy K. Takehara, Amir Ferry, Sara Quon, Brian Koss, Samuel A. Myers, Eric J. Bennett and Ananda W. Goldrath.<\/p>\n
The research was performed in the context of the ImmGenT project within the ImmGen consortium (supported by R24072073). National Institutes of Health grants K00CA222711, GM133351, F31AI176705, DP5OD031863, R35GM148339, R21AI178362, R01AI179952, R37AI067545, R01AI072117 and R01AI150282 supported the research.<\/p>\n
Declaration of interests: Ferry is a co-founder, CEO and board member of TCura Bioscience. Goldrath is a co-founder of TCura Bioscience, Inc., serves on the scientific advisory board of Foundery Biosciences and is a senior advisor to the Allen Institute for Immunology.<\/p>\n","protected":false},"excerpt":{"rendered":"BYLINE: Mario Aguilera Newswise \u2014 T cells are crucial components of our immune system, serving as critical protectors…\n","protected":false},"author":2,"featured_media":426168,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[1380,258,186277,1382,103,61,2747,60,1378,186276,26435],"class_list":["post-426167","post","type-post","status-publish","format-standard","has-post-thumbnail","category-health","tag-all-journal-news","tag-cancer","tag-cell-journal","tag-cell-biology","tag-health","tag-ie","tag-immunology","tag-ireland","tag-newswise","tag-t-cellst-cell-exhaustioncancertumorsproteostasisimmunologyimmunotherapy","tag-university-of-california-san-diego"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/426167","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/comments?post=426167"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/426167\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media\/426168"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media?parent=426167"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/categories?post=426167"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/tags?post=426167"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}