# Mucosal surface and skin protection by MHC class I-based immune regulation

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $383,750

## Abstract

The exposure of the mucosal surfaces and the skin to the environment subjects these tissues to not only
physical injuries and chemical hazards but also microbial damage and immune destruction. Tissue injuries lead
to cascades of inflammatory responses involving both innate and adaptive immune cells systemically in the
lymphoid system and locally in the nonlymphoid target tissues. A well-orchestrated innate and adaptive
immune regulatory response in inflamed tissues is essential for damage control and wound healing. In the
adaptive branch, the CD8 and CD4 lineages of αβ T cells develop in the thymus based on recognition of
antigens presented by MHC class I (MHCI) and MHC class II (MHCII), respectively, yielding a repertoire that
discriminates self from nonself. In the mucosal surfaces and the skin, the symbiosis with microbiota poses a
challenge to the concept of self and nonself discrimination, as the mutualistic microbiota may not fit into the
traditional definition of self or nonself. In a recently-published study of mucosal immune regulation at the
interface with the gut microbiota, we reported the discovery of a novel subset of T cells, MHCI-restricted
CD4+Foxp3+ regulatory T (CI-Treg) cells. They were generated through cross-differentiation from the CD8
lineage to CD4 T cells in a “selfless” mode and effectively controlled mucosal inflammation. CI-Treg cells
recognize MHCI which is broadly expressed in all nucleated tissue cells and typically presents endogenous
tissue antigens, unlike the standard MHCII-restricted CD4 Treg cells which recognize antigens processed
through the exogenous pathway and presented by rare antigen-presenting cells. Microbiota plays a major role
in the expansion / homeostasis of CI-Treg cells. In humans, MHCI-restricted CD4 T cells were identified long
ago in health or disease conditions. However, how CI-Treg cells are generated and how they function in the
mucosal surfaces and the skin remain largely unknown. Our study with a surgical approach in mice revealed
that the mesenteric lymph nodes — which drain the gut mucosae, but not the thymus, were required for CI-Treg
generation. Interestingly, the generation of CI-Treg cells required MHCII, but the cross-differentiated cells
retained the MHCI-restricted specificity. We will use a combination of surgical, molecular and cellular
approaches to investigate the role of microbial and host signals in generation and homeostatic expansion of
CI-Treg cells. We will also examine the function of CI-Treg cells in protecting the mucosal surfaces and the skin
from chemically-induced inflammatory damage, immune-mediated destruction, or inflammatory injury initiated
by physical obstruction. The knowledge from this study will help design future interventions to control
inflammatory tissue damage in the mucosal surfaces and the skin.

## Key facts

- **NIH application ID:** 9820715
- **Project number:** 5R01AI134903-02
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Zhibin Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 5
- **Project period:** 2018-11-15 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9820715

## Citation

> US National Institutes of Health, RePORTER application 9820715, Mucosal surface and skin protection by MHC class I-based immune regulation (5R01AI134903-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9820715. Licensed CC0.

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