Nature Communications<\/a>\u00a0has the potential to refine and expand T cell therapies.<\/p>\n\u201cThis new fundamental understanding of how the signaling system works may help re-engineer that next generation of treatments,\u201d says first author Ryan Notti, an instructor in clinical investigation in the lab and a special fellow in the medicine department at Memorial Sloan Kettering Cancer Center, where he treats patients with sarcomas, or cancers that arise from soft tissue or bone.<\/p>\n
\u201cThe T cell receptor is really the basis of virtually all oncological immunotherapies, so it\u2019s remarkable that we use the system but really have had no idea how it actually works\u2014and that\u2019s where basic science steps in,\u201d says Walz, a world expert in cryo-EM imaging. \u201cThis is some of the most important work to ever come out of my lab.\u201d<\/p>\n
Walz\u2019s lab specializes in visualizing macromolecular complexes, particularly cell membrane proteins, which mediate interactions between the cell interior and exterior. The TCR is one such complex. This intricate, multi-protein structure allows T cells to recognize and respond to antigens presented by human leukocyte antigen (HLA) complexes of other cells. It\u2019s this response that T cell therapies have capitalized on to enlist a patient\u2019s own immune system in the cancer fight.<\/p>\n
But while the components of the TCR have been known for decades, the earliest steps of its activation have remained unknown. As a physician-scientist, Notti was frustrated by this knowledge gap: Many of his sarcoma patients were not reaping the benefits of T cell immunotherapies, and he wanted to understand why.<\/p>\n
\u201cDetermining that would help us understand how the information gets from outside the cell, where those antigens are being presented by HLAs, to the inside of the cell, where signaling turns on the T cell,\u201d he says.<\/p>\n
Notti, who received his PhD in structural microbiology at Rockefeller before shifting his focus to oncology, proposed to Walz that they investigate it.<\/p>\n
Walz\u2019s group specializes in designing custom membrane environments that aim to mimic the native environment of specific membrane proteins.<\/p>\n
\u201cWe can change the biochemical composition, the thickness of the membrane, the tension and curvature, the size\u2014all kinds of parameters that we know have an influence on the embedded protein,\u201d Walz says.<\/p>\n
For the study, the researchers aimed to create a native-like environment for the TCR and observe how it behaved. To do so, they put the receptor into a nanodisc, which is a small disc-shaped patch of membrane that is kept in solution by a scaffold protein that wraps around the edge of the disc. It was no mean feat. \u201cGetting all eight of these proteins properly assembled into the nanodisc was challenging,\u201d Notti says.<\/p>\n
All previous structural work on the TCR was performed in detergent, which tends to strip the membrane from the protein. This was the first study in which the complex was put back into a membrane, Walz notes.<\/p>\n
They then began cryo-EM imaging. These images revealed that in its resting state, the T cell receptor had a closed, compacted shape. Once activated by an antigen-presenting molecule, it opened up and extended, as if throwing its arms wide.<\/p>\n
This came as a deep surprise.<\/p>\n
\u201cThe data that were available when we began this research depicted this complex as being open and extended in its dormant state,\u201d Notti explains. \u201cAs far as anyone knew, the T cell receptor didn\u2019t undergo any conformational changes when binding to these antigens. But we found that it does, springing open like a sort of jack-in-the-box.\u201d<\/p>\n
The researchers suggest that combining two key methods made their new view possible. One, they concocted the correct membrane lipid cocktail to replicate the TCR\u2019s in vivo environment. And two, they returned the receptor to that membrane environment using nanodiscs prior to cryo-EM analysis. An intact membrane is key, they discovered, because it holds the TCR in place until activation. By removing the membrane via detergent, previous studies had inadvertently released the latch on the jack-in-the-box, prematurely springing it open.<\/p>\n
\u201cIt was important that we used a lipid mixture that resembled that of the native T cell membrane,\u201d says Walz. \u201cIf we had just used a model lipid, we wouldn\u2019t have seen this closed dormant state either.\u201d<\/p>\n
The researchers are excited about the potential their findings have for optimizing therapies based on T cell receptors.<\/p>\n
\u201cRe-engineering the next generation of immunotherapies tops the charts in terms of unmet clinical needs,\u201d Notti says. \u201cFor example, adoptive T cell therapies are being used successfully to treat certain very rare sarcomas, so one could imagine using our insights to re-engineer the sensitivity of those receptors by tuning their activation threshold.\u201d<\/p>\n
\u201cThis information may be used for vaccine design as well,\u201d Walz adds. \u201cPeople in the field can now use our structures to see refined details about the interactions between different antigens presented by HLA and T cell receptors. Those different modes of interaction might have some implication for how the receptor functions\u2014and ways to optimize it.\u201d<\/p>\n
Source: Rockefeller University<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"Share this Article You are free to share this article under the Attribution 4.0 International license. A new…\n","protected":false},"author":2,"featured_media":256381,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[77],"tags":[110,18,19,4701,17,133,1668],"class_list":{"0":"post-256380","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-science","8":"tag-cancer","9":"tag-eire","10":"tag-ie","11":"tag-immunotherapy","12":"tag-ireland","13":"tag-science","14":"tag-t-cells"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@ie\/115803653715143262","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts\/256380","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/comments?post=256380"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts\/256380\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/media\/256381"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/media?parent=256380"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/categories?post=256380"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/tags?post=256380"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}