Background/Purpose

One key mechanism of peripheral tolerance involves regulatory T cells (Tregs).  Tregs are best known for the expression of the transcription factor Foxp3 that drives many Treg-specific gene expressions.  Defects in Foxp3 expression result in severe autoimmunity, but an increased numbers of Tregs can also be pathologic and contributes to the evasion of tumor surveillance. Thus, the appropriate balance between regulatory and effector T cells is essential to maintain self-tolerance while preserving effective immunity.  How antigen-recognition impacts Treg homeostasis is not known.  The goal of this study is to characterize the peripheral Treg repertoire in healthy people in order to establish the foundation for evaluating Treg homeostatic dysregulation in rheumatoid arthritis and other autoimmune diseases.

Methods

Antigen-specific T cells were identified directly ex vivo using peptide-MHC (pMHC) tetramers.  We selected self-peptides from gp100, citrullinated fibrinogen (cit-Fib), or preproinsulin (PPins) for their relevance in vitiligo, rheumatoid arthritis, and type I diabetes.  Three foreign antigens from the influenza virus (HA, PB1, and PA) were selected for comparison.  Tetramer staining was performed using blood from de-identified healthy blood donors, followed by staining for CD25, CD45RO, Foxp3, and Ki67 expression. Tetramer tagged cells were magnetically enriched and analyzed by flow cytometry. We also compared the frequency of antigen-specific Foxp3+ cells in adult blood versus the cord blood.  

Results

We show vastly different Foxp3 expression between self antigen-specific T cells versus flu-reactive T cells.  On average, 10% of autoantigen-specific T cells express Foxp3, whereas less than 1% of flu-reactive T cells specific for HA are Foxp3+.  This difference is likely due to antigen exposure, because many more HA-specific T cells express Foxp3 in cells from the cord blood. Moreover, the robustness of the T cell response also determines Foxp3 expression.  We examined three distinct flu-reactive T cell populations and found that the frequency of Foxp3+ cells is highest in the least abundant PA-specific T cells, followed by PB1-specific T cells, and lowest in the most highly expanded and memory dominant HA-specific T cells.  In contrast, antigen exposure increases Treg frequency in self-reactive T cell populations, and this correlates with an increase in cellular proliferation. 

Conclusion

These data demonstrate that peripheral homeostasis between Tregs and conventional T cells are regulated by antigen-specificity.  Contextual differences in ligand exposures alter this balance and this has significant implications for autoimmunity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/antigen-specificity-regulates-peripheral-homeostasis-of-regulatory-t-cells/