Immunity Crohn's disease patient T cells respond to intestinal bacteria shift

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with countless microorganisms in the human gut, in healthy people, the immune system exhibits immune tolerance to these symbiotic microorganisms, while in patients with enteritis, the immune system initiates an immuno-inflammatory response to some microorganisms, and the reason for this difference is still unclear
.

The adaptive immune system maintains immune tolerance to intestinal commensal bacteria through the continuous interaction of T cells with microbial antigens
.
T cell tolerance to gut microbes is associated with the tissue microenvironment and is highly
malleable between different T cell types.
However, how T cell fate is time-regulated by gut microbes, and how microbiome-specific T cells participate in protective immunity remains unclear
.
Solving these problems requires knowing the specificity of T cell antigens, tracking T cells in healthy people and patients, and linking
T cell receptor specificity to different immune responses.
However, one problem currently facing researchers is that it is difficult to
identify antigens of microbial origin.

Recently, the Daniel B.
Graham research group and Ramnik J.
Xavier research group from the Broad Institute in the United States published a report entitled The CD4⁺ in Immunity The T cell response to a commensal-derived epitope transitions from a tolerant to an inflammatory state in Crohn's disease article develops a method
for systematically predicting class II-specific epitopes of human leukocyte antigen (HLA) using a humanized bacterial-derived T cell antigen (hBOTA) algorithm 。 A series of microbial epitopes have been identified, of which SusC from Bacteroides is a widely recognizable immunodominant epitope in healthy humans, where SusC activates the IL-10 cytokine response of T cells, manifested as immune tolerance, while in patients with Crohn's disease, SusC activates IL-17A pro-inflammatory factor responses
of T cells.


To solve the problem of difficult discovery of antigens in the human microbiome, the researchers used their previously developed bacterial-derived T cell antigen (BOTA) algorithm [1], based on this, to develop a humanized BOTA pipeline, first by extracting phagosomes in their native state may have topological accessibility of polypeptides, and then by using a set of predefined HLAs Class II alleles perform MHCII binding prediction and identify the corresponding symbiotic immune peptide groups
.

So, by developing the hBOTA algorithm, they identified and discovered microbial epitopes
recognized by human T cells.

Next, to verify that the hBOTA-predicted epitopes can be recognized by immunity, the researchers selected 48 15 peptides encoding the core of the highly popular epitope, called microbiome-associated peptides (MAPs), using peripheral blood mononuclear cells (PBMCs, including T cells, B cells, NK cells, and monocytes) from 40 healthy subjects, and validated them in vitro with synthetic MAPs.
Many previously undiscovered immunologically active T cell epitopes
have been found from countless commensal bacteria.

Intestinal helper T (Th) cells are primarily composed of Th1, Th17 and regulatory T (Treg) cells, so the researchers chose the IFNγ, IL-17A, and IL-10 responses associated with these three T cells as measures of immune activity, with IL-10 being an anti-inflammatory cytokine and IL-17A being a pro-inflammatory cytokine
。 The experimental results showed that all MAPs can significantly activate cytokine responses in at least one subject cell, and 70.
8% of MAPs can significantly activate immune responses in at least 5 subject cells, indicating that most of the MAPs predicted by hBOTA have antigen-specific immune activity
.

Thus, the response of T cells to microbiome epitopes is widespread in healthy subjects and triggers different cytokine responses
.

Treg cells are essential for maintaining gut homeostasis, while Th17 cells maintain tissue integrity and IgA responses in gut homeostasis
.
Therefore, the researchers hypothesized that the ongoing interaction between the commensal antigen and the host gut T cells may manifest as an IL-10 or IL-17A-dominated immune response
.

So they used a dominance score to assess which MAP consistently induced strong IL-10 and IL-17A responses, and of the top 5 MAPs, 4 were predicted to come from TonB-dependent receptor families (TBDRs
).
TBDRs are receptors in the outer membrane of gram-negative bacteria that mediate the transport of many substances, including iron, nickel, vitamin B12, and carbohydrates
.
TBDRs have a common structural feature, namely a transmembrane β-barrel domain and a highly variable plug domain within them, and they found that TBDRs' plug domains are epitope hotspots that can be recognized
by host T cells.

And, to verify their immune activity, they artificially synthesized 4 TBDRs of 22 peptides, TBDRP1-4, covering the epitopes of most plug domains, and could activate PBMCs from 3 healthy subjects, where TBDRP3 could activate a strong IL-10 response
in all 3 subject cells.

When the researchers searched the database, they found that TBDRP3 had a 95.
45% resemblance to many different TBDR-like SusC proteins from the Bacteroides phylum, so they called TBDRP3 a SusC peptide
.
In Bacteroides, the SusC protein is part of the starch utilization system (Sus), encoded by the polysaccharide utilization locus (PUL), responsible for sensing, binding, depolymerizing, and transporting polysaccharides
.
They found that SusC peptide induces a strong T cell IL-10 response in most healthy subject cells, while in PBMCs of origin in patients with Crohn's disease, SusC peptide significantly activates the IL-17A response
of T cells.

Thus, T cells respond to gut symbiotic microbes dynamically, with different cytokine responses in different microenvironments and associated
with immune tolerance.

Finally, they validated in mice that SusC-specific CD4⁺ T cells in the mouse gut exhibit different immune responses depending on their location in the intestinal epithelium or lymphoid tissue, indicating that the dynamic regulation of T cells is associated
with immune tolerance of the intestine to Bacteroides.


Overall, this research develops an antigen-discovery approach that can assess microbe-mediated T cell immune responses under healthy and inflammatory conditions, revealing the dynamic response properties of T cells to symbiotic bacteroides, as well as inflammation-related changes
in patients with Crohn's disease.

Original link:

https://doi.
org/10.
1016/j.
immuni.
2022.
08.
016

Plate Maker: Eleven

References

1.
Graham, D.
B.
 et al.
 Antigen discovery and specification of immunodominance hierarchies for MHCII-restricted epitopes.
 Nat.
Med.
 24, 1762–1772 (2018).

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