- Self-antigen-specific T cells in the mature adaptive immune system are regulated through multiple mechanisms of tolerance, but inflammatory conditions may allow them to break tolerance and trigger autoimmunity
- In this study, peptide:major histocompatibility complex tetramers were used to rigorously track the behavior of endogenous CD4+ T cells with specificity to a lung-expressed self-antigen in mouse models of immune-mediated lung injury
- Lung injury induced self-antigen-specific regulatory T (Treg) cells to expand and localize to the damaged tissue expressing the self-antigen, and this process was dependent on specific recognition of self-antigen and the presence of the cytokine IL-2
- The self-antigen-specific CD4+ T-cell repertoire seems poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity
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.
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 Tregs
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 (Treg) cell phenotype that suppressed inflammation.
Preferential activation of self-antigen-specific CD4+ Treg 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 Tregs was dependent on T-cell receptor and interleukin-2 signaling.
Generalized Tissue Injury Model
After intranasal LPS administration, Foxp3+ Treg 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 Treg ablation similarly fared worse after intranasal LPS administration.
These results imply that expansion and localization of Treg cells at the site of tissue damage may arise from T-cell clones that harbor self-reactivity and that such Treg cells are important in regulating the ongoing inflammation.
The self-antigen-specific CD4+ T cells that polarize toward a regulatory fate seem to represent a larger repertoire of self-reactive Tregs that mobilize in response to tissue injury and help regulate further tissue damage. Further research into the mechanisms underlying the preferential expansion of these Tregs and characterization of their effector functions should provide insight into potential therapeutic strategies for modulating self-reactive Tregs in human disease.
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