Biochemical controls: T cell receptors control gut immunity (Introduction)

by David Turell , Friday, July 05, 2024, 16:40 (64 days ago) @ David Turell

A careful bacterial study:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/05_july_2024/420538...

"It has been challenging, however, to pinpoint specific bacteria that exert host-associated effects, as human stools typically consist of hundreds of microorganisms and are highly person specific. As a complementary approach to fecal transplantation, researchers have used monocolonization (colonizing animals with a single bacterial isolate), to identify specific bacterial mechanisms of action. Although monocolonization can identify bacterial strains capable of modulating immune cells, it neglects the fact that a strain exerts different functions when coexisting with other bacterial species such as in a complex, native-scale microbial community.

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"As a starting point for our recent work (5), we asked whether a complex bacterial community mimics the function of a natural microbiome....this finding shows that a complex defined community can be used as a model system to interrogate immune modulation by the gut microbiome.

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"After coculturing, we quantified the number of T cells activated by measuring Nur77 expression, a sensitive marker of T cell receptor (TCR) stimulation. The data were intriguing—a markedly higher percentage of T cells were stimulated by bacterial strains than expected, and the sum of all the stimulated T cells was far greater than 100%. The result was inconsistent with the hypothesis that a TCR is specific to one strain in the community. Instead, this result suggests that one T cell can recognize multiple bacterial strains simultaneously.

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"After running more than 11,000 assays, we obtained the TCR-strain specificity data, which revealed that nearly all the TCRs tested are specific for multiple strains in the community.

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"Our system has three notable features: (i) Complexdefined communities are manipulable, and we can test the function of every strain in the physiological context of other members; (ii) coculturing individual commensals with TCRs makes it possible to map immune phenotypes and bacterial strains at a high resolution; and (iii) a rapid generation of TCR cell lines identifies TCR–antigen pairs to reveal molecular-level interactions.

"The gut microbiome consists of a vast number of microorganisms. Prophylactic protection against all of them is a challenge for the adaptive immune system. The one-to-many TCR–bacteria relationship explains how a small number of TCRs work as a “blockbuster” to respond to many commensals in the community by recognizing a widely conserved antigen. This model corresponds in part to the characteristics of broadly neutralizing antibodies against HIV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) (9, 10). The recognition is specific at the molecular level but provides broad protection against microbes because their targets are widely conserved. This discovery presents a therapeutic opportunity to skew gut immune reaction toward tolerance or inflammation by manipulating microbiome-specific T cell response."

Comment: the degree of T cell sensitivity to different bacteria is amazing. Chance mutations did not develop this; only design can.