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Beyond FOXP3: gut tolerogenic CD8+ T cells

Tingyue Zhou , Shu Zhu

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Vita > Cutting Edge > DOI: 10.15302/vita.2026.07.0058
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Beyond FOXP3: gut tolerogenic CD8+ T cells

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Inflammatory bowel disease (IBD) afflicts more than 10 million people worldwide, and this number is rising sharply1, yet its pathogenic mechanisms remain elusive, leaving a lack of precise drug targets. A recent Nature study by Cui et al.2 identifies a novel population of immunoregulatory CD8+ T cells strongly linked to IBD, advancing our understanding of the disease's etiology and revealing that T cell subsets beyond FOXP3-expressing regulatory T cells3, such as CD8+ T cells, also play important roles in human peripheral tolerance.

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The intestine harbors abundant commensal microorganisms and dietary components. The intestinal immune system must defend against pathogenic invasion while maintaining immune tolerance to microbial and dietary constituents that are likewise recognized as non-self. Breach of this tolerance triggers uncontrolled immune responses that cause various diseases including IBD. Regulatory T (Treg) cells, a CD4+ T cell subset expressing FOXP3, are considered the principal mediators of immune regulation in the gut; however, FOXP3+ Treg cells are not numerically deficient but rather moderately expanded in inflamed IBD mucosa, yet this expansion appears insufficient to control inflammation4. This paradox — persistent inflammation despite Treg presence — suggests that additional regulatory mechanisms may contribute to maintaining mucosal immune homeostasis and preventing IBD pathogenesis. Cui et al.2 identified a distinct population of regulatory CD8+ T cells in the intestine (Fig. 1); because GPR15 serves as their marker and mediates their homing to the gut, these cells were termed intramucosal GPR15-guided regulatory CD8+ T lymphocytes (CD8+ TIGR). The association between this population and IBD may explain the potential cause of IBD development in certain individuals.
IBD pathogenesis is shaped by both genetic and environmental factors. To identify genetic causes, the authors investigated seven patients from four unrelated families with early-onset IBD and performed whole-exome sequencing, revealing that all families carried potentially deleterious GPR15 variants. These included compound heterozygous (p.D306N/p.Q281X), homozygous stop-gain (p.Y215X), and homozygous missense (p.Y132S/p.F159I) mutations distributed across the protein, with a clear gene-dosage effect: biallelic carriers developed severe pan-colitis whereas monoallelic carriers exhibited milder, localized disease, and penetrance was incomplete. Mechanistically, these mutations impaired GPR15 surface expression, intracellular trafficking to the plasma membrane, and GPR15L-stimulated calcium influx and migration. Beyond the index families, retrospective analysis of Turkish, Qatari, and Iranian cohorts, together with population-level burden testing in Genebass and the All of Us biobank, confirmed that deleterious GPR15 variants — including predicted loss-of-function alleles — are significantly associated with IBD and related colonic phenotypes.
The authors further investigated how GPR15 influences IBD development. Despite prior assumptions that GPR15 guides CD4+ Treg homing, FOXP3+ Treg cells were abundant in patient colons. Instead, they observed a profound and selective deficit of CD8+ T cells in the colonic epithelium and lamina propria of both patients carrying GPR15 mutations and Gpr15 knockout mice. Adoptive transfer experiments confirmed that Gpr15 variants cell-autonomously impair the colonic homing of CD8+ T cells rather than CD4+ Treg cells.
Utilizing single-cell RNA sequencing, the researchers characterized this GPR15-expressing CD8+ T cell population as a unique subset, officially coining them CD8+ TIGR cells. Crucially, CD8+ TIGR cells are evolutionarily conserved across humans and mice, sharing distinct transcriptional signatures enriched for NK-associated receptors (e.g., KIRs, Ly49) and immunosuppressive genes (e.g., ZFP36, NFKBIA), fundamentally differentiating them from classic cytotoxic T cells or previously defined peripheral regulatory CD8+ T cells. Using a DSS-induced mouse colitis model, the authors further confirmed that Gpr15 loss in CD8+ T cells causes colitis. Crucially, selective deletion of Gpr15 in CD8+ T cells, but not in Treg cells, exacerbated DSS-induced colitis, demonstrating that TIGR rather than Treg cells mediate this protection and play a critical role in suppressing intestinal inflammation.
The authors next explored how TIGR exert immunosuppression and discovered that they kill macrophages to suppress inflammation. In active IBD, macrophages accumulate and drive inflammation; patient biopsies showed marked increases in CD68+, CD11c+, and HLA-DR+ macrophages, and Gpr15–/– mice exhibited expanded, activated F4/80+ macrophages whose clodronate-mediated depletion attenuated colitis. In vitro, activated CD8+ TIGR rapidly killed LPS-activated macrophages in a cell-contact-dependent manner. This killing relied on Fas ligand (FasL) and TNF-related weak inducer of apoptosis (TWEAK), whereas perforin, TNFα, IFNγ, and TRAIL were dispensable. Notably, blocking class I MHC did not affect cytotoxicity, indicating that killing is independent of TCR-specific antigen recognition and instead resembles innate lymphocyte-like function. Thus, TIGR cells restrain intestinal inflammation by selectively eliminating inflammatory macrophages through an innate-like, antigen-independent cytotoxic mechanism.
Although the immunoregulatory function of TCRαβ+CD8αα+ IELs has been studied in mice5, the equivalent subset and its function in humans have remained unclear, as TCRαβ+CD8αα+ IELs are absent from the human intestine. Mouse TIGR cells, which constitute a regulatory TCRαβ+CD8αα+ IEL subset, share highly conserved features with TIGR cells in the human gut; the identification of TIGR therefore confirms the immunoregulatory function of CD8+ IELs in humans. Although the function of TIGR cells has been characterized in considerable detail, defining their antigen specificity and determining whether their development is shaped by local intestinal antigen-presenting cells would further illuminate the developmental pathway of this population and facilitate the therapeutic targeting of TIGR cells for IBD treatment.
Moreover, the identification of TIGR underscores that the gut, as the frontline of tolerance establishment, relies on a greater diversity of cell types beyond FOXP3+ Treg cells to mediate immune regulation and restrain uncontrolled inflammation. Indeed, in mice, intestinal CD4+CD8αα+ IELs mediate immune tolerance to commensal microorganisms6, whereas FOXP3–IL-10+ TR1 cells maintain tolerance to food antigens7,8. Why does the gut require multiple types of regulatory T cells beyond Treg cells? One plausible explanation is that the diverse array of antigens within the intestinal lumen creates a complex immune environment that demands distinct regulatory T cell populations to suppress inflammation triggered by different types of effector cells. Different regulatory T cell subsets may exhibit distinct suppressive preferences; for instance, TIGR cells preferentially suppress macrophages rather than dendritic cells2. Furthermore, different regulatory T cell subsets occupy distinct spatial niches within the gut — Treg cells reside predominantly in the lamina propria, whereas TIGR cells localize to the epithelial layer — a compartmentalization that likely underlies their division of labor in mediating immune tolerance across different tissue compartments. Elucidating the fine-tuned interplay among the diverse regulatory T cell populations in the gut may represent a key focus for future research, and a clearer mechanistic understanding of tolerance establishment will further advance our comprehension of the pathogenesis of intestinal immune-related diseases such as IBD, colorectal cancer, and food allergy.

[1]

Hracs, L. et al. Nature 642, 458–466 (2025).

[2]

Cui, J. et al. Nature https://doi.org/10.1038/s41586-026-10749-4 (2026).

[3]

The Nobel Assembly at Karolinska Institutet. Immune tolerance: the identification of regulatory T cells and FOXP3. Accessed July 27, 2026. Available at the website of nobelprize.org/prizes/medicine/2025/press-release/ (2025).
[4]

Maul, J. et al. Gastroenterology 128, 1868–1878 (2005).

[5]

Cheroutre, H., Lambolez, F. & Mucida, D. Nat. Rev. Immunol. 11, 445–456 (2011).

[6]

Bousbaine, D. et al. Science 377, 660–666 (2022).

[7]

He, K.X. et al. Cell 186, 3033–3048.e20 (2023).

[8]

Zhou, T.Y., Zhang, G.R., Wu, C.Y., Wan, T.T. & Zhu, S. BioRxiv https://doi.org/10.1101/2025.07.23.666039 (2025).

RIGHTS & PERMISSIONS

The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Zhou, T., Zhu, S.  Beyond FOXP3: gut tolerogenic CD8+ T cells  Vita https://doi.org/10.15302/vita.2026.07.0058 ()
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