CD8+ Regulatory T Cell – A Mystery to Be Revealed

Abstract

Regulatory T cells (Treg) are essential to maintain immune homeostasis and prevent autoimmune disorders. While the function and molecular regulation of Foxp3+CD4+ Tregs are well established, much of CD8+ Treg biology remains to be revealed. Here, we will review the heterogenous subsets of CD8+ T cells have been named “CD8+ Treg” and mainly focus on CD122hiLy49+CD8+ Tregs present in naïve mice. CD122hiLy49+CD8+ Tregs, which depends on transcription factor Helios and homeostatic cytokine IL-15, have been established as a non-redundant regulator of germinal center (GC) reaction. Recently, we have demonstrated that TGF-β (Transforming growth factor-β) and transcription factor Eomes (Eomesodermin) are essential for the function and homeostasis of CD8+ Tregs. In addition, we will discuss several open questions regarding the differentiation, function and true identity of CD8+ Tregs as well as a brief comparison between two regulatory T cell subsets critical to control GC reaction, namely CD4+ TFR (follicular regulatory T cells) and CD8+ Tregs.

Regulatory T cells (Tregs) in lymphoid malignancies and the impact of novel therapies

“…CD8 + Tregs that express FoxP3 and exhibit suppressive function have been identified, but research on this rare subset is limited ( 82 ). CD8 + CD25 + FoxP3 + Tregs have been noted to be increased in CLL patients compared to healthy donors ( 79 ) as well as in progressive versus indolent CLL patients ( 83 ).…”

Anti-CAIX BBζ CAR4/8 T cells exhibit superior efficacy in a ccRCC mouse model

“… 32 Consequently, we studied the distribution of Treg cells among the three CAR8 groups, revealing that the presence of 4-1BB significantly inhibited the differentiation of CD8 Treg cells ( Figures 4 B and 4C), which were defined by overexpression of FOXP3 and IL-2RA (CD25). 33 , 34 …”

Helios Expression Is Downregulated on CD8+ Treg in Two Mouse Models of Lupus During Disease Progression

“…Among the different CD8 + Treg cell subsets defined ( 51 , 52 ), we focused on CD8 + Tregs expressing the triad of the CD44, CD122, and Ly49 surface markers (in addition to Helios) due to their presence in steady-state naïve animals and their reported implications in the lupus-like phenotypes ( 12 , 15 ), as well as in other autoimmune models ( 17 , 53 ), and their very recent description in human autoimmunity as KIR + CD8 + T cells ( 9 ). In this sense, although other CD8 + Treg populations have been described with important roles in cell therapy, such as CD8 + CD103 + ( 54 ), CD8 + FoxP3 + , and CD8 + CD28 − Tregs ( 55 ), most of them are essentially induced in vitro and barely in young unmanipulated mice, unlike CD8 + Tregs [CD44 + CD122 + Ly49 + ( 12 , 52 )].…”