T Cells With Known Specificity Used to Determine the Treg Response in Lung Injury

During development, many conventional self-antigen-specific T cells mature in the peripheral immune system. In their steady state, these T cells are heavily regulated by multiple overlapping mechanisms of tolerance. However, inflammatory conditions such as tissue injury may allow the cells to break tolerance and trigger autoimmunity.

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James J. Moon, PhD, a principal investigator in the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital, Daniel S. Shin, MD, PhD, a postdoctoral fellow in the Moon Lab, and colleagues recently characterized how the activation of self-antigen-specific T cells occurs during the early stages of inflammatory tissue injury. In Cell Reports, they present crucial insights into how steady-state peripheral tolerance may fail under inflammatory conditions.

Methods

Studying the physiologic response of self-antigen-specific T cells upon recognition of their cognate antigen during inflammation is technically challenging because there are extremely low frequencies of T cells specific for any given antigen.

To overcome this barrier, the Moon Lab has developed the use of peptide:major histocompatibility complex (MHC) tetramer-based cell enrichment techniques with model antigen-bearing mice to directly identify and analyze endogenous self-antigen-specific T-cell populations that are regulated in the steady state in a tissue-specific manner.

In this study, they used that system to directly address how immune-mediated lung injury in the mice leads to activation of endogenous self-antigen-specific CD4+ T cells.

Expansion of Self-Antigen-Specific T_regs

In response to self-antigen presentation during acute lung injury from the infusion of autoreactive CD4+ T cells, the team observed an expansion of host CD4+ T cells almost exclusively within the Foxp3-expressing compartment. This resulted in a strong skewing of the self-antigen-specific population toward a CD4+ regulatory T (T_reg) cell phenotype that suppressed inflammation.

Preferential activation of self-antigen-specific CD4+ T_reg cells was also seen in:

• A pancreatic self-antigen model
• Lung injury from CD8+ T cell–mediated autoimmunity
• An antigen-free model of acute lung injury produced by Escherichia coli–derived lipopolysaccharide (LPS)

The expansion of self-antigen-specific T_regs was dependent on T-cell receptor and interleukin-2 signaling.

Generalized Tissue Injury Model

After intranasal LPS administration, Foxp3+ T_reg cells were not detected within the lungs of mice that harbored a peripheral T-cell repertoire with limited self-antigen specificity, and those mice experienced more weight loss than mice with normal repertoires.

Mice treated with an interleukin-2–blocking antibody or experienced T_reg ablation similarly fared worse after intranasal LPS administration.

These results imply that expansion and localization of T_reg cells at the site of tissue damage may arise from T-cell clones that harbor self-reactivity and that such T_reg cells are important in regulating the ongoing inflammation.

Commentary

The self-antigen-specific CD4+ T cells that polarize toward a regulatory fate seem to represent a larger repertoire of self-reactive T_regs that mobilize in response to tissue injury and help regulate further tissue damage. Further research into the mechanisms underlying the preferential expansion of these T_regs and characterization of their effector functions should provide insight into potential therapeutic strategies for modulating self-reactive T_regs in human disease.

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