Inhibition of follicular T-helper cells by CD8+ regulatory T cells is essential for self tolerance

Abstract

Analysis of the immune system has defined a subset of CD4+ T cells, termed CD4+ Treg, that can inhibit excessive inflammatory immune responses. However, no T cells genetically programmed to inhibit autoantibody formation and systemic-lupus-erythematosus-like disease have so far been defined. A mechanism fitting that description has now been identified in mice. A subset of CD8+ T cells (CD8+ Treg) is shown to prevent autoantibody formation and maintain self-tolerance in a process that involves recognition of Qa-1 peptide ligands expressed at the surface of follicular helper T cells. A detailed understanding of this aspect of immune-system regulation could lead to new approaches for the treatment of systemic lupus erythematosus and other autoimmune disorders. Immune cells that recognize 'self' tissues need to be eliminated or controlled in order to prevent autoimmune diseases. Here, a T-cell population is delineated that is necessary to maintain self tolerance in mice. Genetic disruption of the inhibitory interaction between these CD8+ T cells and their target Qa-1+ follicular T-helper cells results in a lethal systemic-lupus-erythematosus-like autoimmune disease. The ability to produce vigorous immune responses that spare self tissues and organs depends on the elimination of autoreactive T and B cells. However, purging of immature and mature self-reactive T and B cells is incomplete and may also require the involvement of cells programmed to suppress immune responses1. Regulatory T cells (Treg) belonging to the CD4+ T-cell subset may have a role in preventing untoward inflammatory responses, but T-cell subsets programmed to inhibit the development of autoantibody formation and systemic-lupus-erythematosus-like disease have not yet been defined2. Here we delineate a CD8+ regulatory T-cell lineage that is essential for the maintenance of self tolerance and prevention of murine autoimmune disease. Genetic disruption of the inhibitory interaction between these CD8+ T cells and their target Qa-1+ follicular T-helper cells results in the development of a lethal systemic-lupus-erythematosus-like autoimmune disease. These findings define a sublineage of CD8 T cells programmed to suppress rather than activate immunity that represents an essential regulatory element of the immune response and a guarantor of self tolerance.