免疫系の「平和維持細胞」が自己免疫疾患を防ぐ役割(“Peacekeeper” cells play important role in preventing autoimmune disease)

2025-05-09 シカゴ大学(U Chicago)

<関連情報>

• https://news.uchicago.edu/story/peacekeeper-cells-play-important-role-preventing-autoimmune-disease
• https://www.science.org/doi/10.1126/science.adk3248

T細胞を制御する制御性T細胞が、感染時に寛容をもたらす特異性を共有するT細胞を拘束する Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection

David E. J. Klawon, Nicole Pagane, Matthew T. Walker, Nicole K. Ganci, […] , and Peter A. Savage
Science  Published:27 Feb 2025
DOI:https://doi.org/10.1126/science.adk3248

Editor’s summary

Regulatory T (T_reg) cells dampen the activity of conventional T (T_conv) cells to limit excessive and inappropriate tissue damage. Klawon et al. used mouse models to investigate the role of T_reg cells that recognized the same prostate tissue peptide antigen as T_conv cells. In immune responses accompanied by increased availability of prostate antigen, deletion of prostate-specific T_reg cells increased the infiltration of the matched T_conv cells into the prostate. Thus, in this context, nonmatched T_reg cells could not restrain self-reactive T_conv cells. Rather, the self-recognizing T_reg cells proliferated earlier in response to antigen than their T_conv counterparts, helping to curb their activity. —Sarah H. Ross

Structured Abstract

INTRODUCTION

A fundamental feature of the adaptive immune system is its ability to generate immunity to foreign pathogens while restricting collateral damage to self-tissues, a property referred to as self-nonself discrimination. In the T cell compartment, this effect is conferred in part by the purging or inactivation of conventional T (T_conv) cells exhibiting strong reactivity to self-peptides complexed with host major histocompatibility complex (MHC) molecules (self-pMHC). However, despite these mechanisms, self-pMHC–reactive T_conv cells with pathogenic potential persist, requiring continuous control by Foxp3-expressing regulatory T (T_reg) cells to prevent autoimmunity.

RATIONALE

This observation highlights a fundamental unanswered question that sits at the nexus of protective immunity and autoimmunity: During infection, in which both self- and pathogen-derived peptides are presented in an inflammatory environment permissive for T cell activation, how do T_reg cells selectively control T_conv cells reactive to self-peptides while simultaneously enabling robust T cell responses to pathogen-derived peptides? Conventional modes of T_reg cell suppression—such as sequestration of costimulatory ligands, local hoarding of secreted factors, and production of suppressive cytokines—function broadly without regard to the peptide specificity of responding T cells. Therefore, these mechanisms lack the selectivity needed to distinguish between self- and nonself-reactive T_conv cells. To address this gap, we examined the hypothesis that T_reg cells reactive to self-peptides selectively constrain T_conv cells of matched specificity during infection, thereby enforcing self-nonself discrimination.

RESULTS

Through the study of CD4⁺ T cell responses to a natural prostate-specific self-peptide, we identified two tiers of T_reg cell–mediated regulation. T_reg cells of matched specificity were not required for the control of self-peptide–reactive T_conv cells at steady state or after innate immune activation. However, such T_reg cells became crucial in a setting of pathogen-associated epitope mimicry, in which levels of both innate activation and self-peptide presentation rise concurrently. When self-peptide–specific T_reg cells were present, mice were protected from autoimmunity after infection with a bacterium expressing the self-peptide. In the absence of such T_reg cells, infection induced extensive autoimmunity of the prostate. T_reg cells reactive to the self-peptide did not prevent the priming of T_conv cells of shared specificity but instead stifled their subsequent proliferation and differentiation. The expansion of self-peptide–reactive T_reg cells occurred earlier than that of T_conv cell counterparts, suggesting that antigen-activated T_reg cells were intrinsically poised to accumulate more rapidly, thereby providing a numerical advantage in the early stages of the response. Quantitative imaging revealed heterogeneous patterns of T_reg cell–mediated control; some self-pMHC–specific T_conv cells were restrained by locally enriched polyclonal T_reg cells, whereas others required the local enrichment of T_reg cells of shared specificity to attenuate T cell receptor (TCR) and interleukin-2 (IL-2) signaling, thereby stifling proliferation and effector differentiation. Notably, T_reg cell–mediated control of self-peptide–reactive T_conv cells had no impact on the T_conv cell response to pathogen-derived nonself peptides, demonstrating self-peptide specificity of the observed suppression.

CONCLUSION

The selective control of self-peptide–reactive T_conv cells by T_reg cells of matched specificity may be especially relevant for immunological insults that are proposed drivers of autoimmunity, including pathogen-associated epitope mimicry or the release of self-antigens and inflammatory signals triggered by infection-induced cell death. These findings support a T_reg cell–centric model of self-nonself discrimination in which the immune system generates T_reg cells reactive to highly antigenic self-peptide ligands, selectively focusing immunosuppression on T_conv cells of matched specificity during strong immunological challenges. This model complements and advances classical paradigms of self-nonself discrimination, illustrating how the adaptive immune system operates on a knife’s edge between effective pathogen control and the risk of autoimmunity during infection.

OPEN IN VIEWER

T_reg cells enforce self-nonself discrimination during infection by selectively constraining T_conv cells of shared self-specificity.

Upon infection with a pathogen expressing a self-peptide—a model of pathogen-associated epitope mimicry or elevated self-antigen elicited by tissue damage—self-peptide–specific T_reg cells selectively control CD4⁺ T_conv cells reactive to the same peptide by attenuating TCR stimulation, IL-2 signaling, and proliferation. This selective suppression simultaneously prevents autoimmunity and enables robust T_conv responses against foreign pathogen–derived peptides to protect the host.

Abstract

During infections, CD4⁺ Foxp3⁺ regulatory T (T_reg) cells must control autoreactive CD4⁺ conventional T (T_conv) cell responses against self-peptide antigens while permitting those against pathogen-derived “nonself” peptides. We defined the basis of this selectivity using mice in which T_reg cells reactive to a single prostate-specific self-peptide were selectively depleted. We found that self-peptide–specific T_reg cells were dispensable for the control of T_conv cells of matched specificity at homeostasis. However, they were required to control such T_conv cells and prevent autoimmunity toward the prostate after exposure to elevated self-peptide during infection. Notably, the T_reg cell response to self-peptide did not affect protective T_conv cell responses to a pathogen-derived peptide. Thus, self-peptide–specific T_reg cells promoted self-nonself discrimination during infection by selectively controlling T_conv cells of shared self-specificity.