Inflammatory bowel disease (IBD), which incorporates ulcerative colitis (UC) and Crohn’s disease (CD), is related to mucosal inflammation that arises because of abnormal immune cell activation. A recent study in Nature Medicine traces the sources of such a inflammation to yeast cells.

Study: Collection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic TH1 cell responses in Crohn’s disease. Image Credit: Kateryna Kon / Shutterstock.com

Introduction

IBD is characterised by abnormal immune responses causing inflammation of the gastrointestinal (GI) tract wall. These immune responses are driven by CD4+ T-cells reactive to gut microorganisms; nonetheless, their specific targets are unknown.

Since IBD causes chronic and significant illness and reduces patients’ quality of life, researchers have attempted to discover each the microbial targets and T-cell phenotypes involved in these conditions, especially as they might vary between subgroups.

T helper (TH) cells of the TH17 subtype are regulatory in function, as they modulate potentially harmful inflammatory immune responses to pathogens. The impairment of this function may arise because of higher levels of interleukin (IL)-17A-producing T-cells within the intestinal mucosa of patients with IBD. Nevertheless, IL-17 antagonists haven’t been effective in CD and have worsened the condition in some patients.

TH17 cells may act otherwise in numerous situations. For instance, if TH17 cells also express interferon (IFN)-γ or granulocyte-macrophage colony-stimulating factor (GM-CSF), these cells could turn out to be pathogenic reasonably than protective. Notably, IFN-γ-positive TH1 cells are at all times raised within the gut mucosa of CD but not UC patients.

Fungi are a part of the gut microbiome, with yeast like Candida albicans, a key commensal microorganism that regulates the immune response. In truth, Candida albicans induces TH17 cells, thereby promoting the secretion of mucosal antibody immunoglobulin A (IgA) from the gut mucosa and systemic IgG antibodies.

It stays unknown if these yeast cells are the result or explanation for inflammation in these patients. Notably, Saccharomyces cerevisieae, also known as ‘baker’s yeast’ antibodies (ASCA,) have been reported within the blood of CD patients and are able to binding to C. albicans antigens.

The present study examined how yeast within the GI tract affects CD4+ T-cell responses and contributes to inflammation in CD.

What did the study show?

An increased CD4+ T-cell response attributable to yeast reactivity was observed in CD patients. Between 50-60% of those patients exhibit ASCAs of their serum, which is taken into account a marker of disease severity.

Upon comparing IgA/IgG ASCA levels, a big rise in T-cell reactivity to multiple yeasts in CD patients with ASCA was observed. This response was absent in ASCA-negative CD patients. Conversely, each CD subgroups responded strongly to the presence of C. albicans with T memory cell responses.

These yeast-reactive T-cells are also present within the inflamed gut mucosa of ASCA-positive CD patients but are absent in healthy tissues of the identical patients and in all tissues from ASCA-negative individuals with CD. These T-cells exhibited increased reactivity to yeast species which are occasionally used to treat IBD as a probiotic but less so to C. albicans.

In ASCA-positive CD patients, an intense inflammatory yeast-reactive TH1 cell response was observed. These cells also secrete higher levels of IFN-γ, with this increased secretion more notable against fungi aside from C. albicans. Inflammatory cytokines were also increased against certain yeasts.

In CD patients exposed to commensal or food-derived yeasts, yeast-reactive CD4+ T-cells developed a cytotoxic TH1 effector cell phenotype. This didn’t look like the results of a conversion of TH17 cells reactive to C. albicans into TH1 cells. Cytotoxic T lymphocytes (TH1 CTLs) from ASCA-positive CD patients were able to killing gut epithelial cells.

Altered TH1-like phenotypes were observed in yeast-reactive CD4+ T-cells in close relatives of CD patients with IBD; nonetheless, these individuals were clinically unaffected. This will indicate a stage-wise development of cytotoxic capability, because the cells are presented repeatedly with yeast antigens because of the increased permeability of the gut mucosa previously reported in such individuals.

The importance of cytotoxic TH1 cell responses is probably going attributed to their clonal expansion, coupled with their high reactivity to multiple yeast species, including those present at lower abundances. Thus, these clones are likely chosen by repeated interactions with conserved antigens that remain unchanged across multiple yeast species.

This results in abnormal CD4+ T-cell reactivity in CD patients. Being cross-reactive, these cells remain chronically activated within the presence of a spread of yeasts, which ends up in a cytotoxic phenotype. This accounts for the chronic nature and resistance to treatment seen in CD.

What are the implications?

Yeasts appear to contribute to a big increase in TH1 cytotoxic cell responses that result in the inflammatory immune response observed in a subgroup of CD patients. Further work is required to discover the unique explanation for the TH1 response since C. albicans plays a homeostatic role in T-cell immunity and regulatory TH17 cell responses.

The chronic activation of those cells by various non-albicans fungi leads to the clonal expansion of cross-reactive CD4+ TH1 cells that recognize conserved antigens in lots of yeasts. Each commensal and food-derived fungi may contribute to the eventual TH1 CTL response; nonetheless, TH17 cells reactive to C. albicans appear to withstand such influences.

These yeast-reactive T-cells could provide therapeutic targets for the treatment of CD, perhaps by T-cell depletion or by T regulatory cells specific to those antigens.

This might reveal a general mechanism of how number of cross-reactive T cells may allow adaptive immunity to deal with the large diversity of microbial antigens which, if not properly regulated, could come on the expense of fostering chronicity and contribution to therapy resistance in IBD because of persistent antigen activation.”

Journal reference:

• Martini, G. R., Tikhonova, E., Rosati, E., et al. (2023). Collection of cross-reactive T cells by commensal and food-derived yeasts drives cytotoxic TH1 cell responses in Crohn’s disease. Nature Medicine. doi:10.1038/s41591-023-02556-5.