TGF-β and Eomes control the homeostasis of CD8+ regulatory T cells

Abstract

In addition to Foxp3+ CD4+ regulatory T cells (CD4+ T reg cells), Foxp3− CD8+ regulatory T cells (CD8+ T reg cells) are critical to maintain immune tolerance. However, the molecular programs that specifically control CD8+ but not CD4+ T reg cells are largely unknown. Here, we demonstrate that simultaneous disruption of both TGF-β receptor and transcription factor Eomesodermin (Eomes) in T cells results in lethal autoimmunity due to a specific defect in CD8+ but not CD4+ T reg cells. Further, TGF-β signal maintains the regulatory identity, while Eomes controls the follicular location of CD8+ T reg cells. Both TGF-β signal and Eomes coordinate to promote the homeostasis of CD8+ T reg cells. Together, we have identified a unique molecular program designed for CD8+ T reg cells.

A new chapter in the CD8 T reg story

“…Possibly, TGF-β-dependent up-regulation of Helios during early maturation of CD8 T reg cells avoids deletion of these autoreactive cells in the thymus (Nakagawa et al, 2018). Mishra et al (2020) also note that deficient TGF-β signaling impairs Helios expression by CD8 T reg cells but not CD4 + FoxP3 + T reg cells (T FR ), suggesting that distinct lineagespecific inducing signals may control Helios expression in the two regulatory cell types. Separate genetic programing of the two T reg cell subsets is consistent with the distinct and complementary roles they play in maintaining self-tolerance and regulating autoantibody responses.…”

“…For example, expression of the central T FH transcription factor Bcl-6 by FoxP3 + CD4 T reg cells allows T FR cells to migrate toward GC where they interact with target cells. Mishra et al (2020) show that Eomes-dependent expression of CXCR5 by CD8 T reg cells allows them to locate into secondary lymphoid follicles, where they may efficiently suppress/target T FH cells. Since Eomes expression also promotes survival and expansion of self-reactive CD8 T cells, perhaps by up-regulation of Bcl-2 (Castro et al, 2011;Miller et al, 2020), the Eomes TF may contribute to both appropriate homing as well as survival of CD8 T reg cells during the GC response.…”

“…However, the genetic basis for these properties of CD8 T reg cells has been uncertain. Mishra et al (2020) show that deletion of Tgfbr2 in T cells (Tgfbr2 f/f dLckcre) results in failed expression of the Helios TF, which has been implicated in their regulatory identity and survival (Kim et al, 2015).…”

“…When is the TGF-β signal required for CD8 T reg cell differentiation? Mishra et al (2020) have examined the effects of TGF-β signaling on CD8 T reg cell differentiation after deletion of Tgfbr2 expression in peripheral T cells. Previous studies of the effects of TGF-β signaling on thymic differentiation using Tgfbr2 f/f CD4-Cre mice revealed a sharp reduction of CD44 + CD122 + Ly49 + CD8 single-positive thymocytes and evidence that the TGF-β signaling pathway may regulate early stages of CD8 T reg cell selection and differentiation (McCarron and Marie, 2014).…”

“…In this issue, Mishra et al (2020) report that TGF-β signaling and Eomes-dependent genetic programming are essential to the development and maintenance of CD8 T reg cells. Mice deficient in both the TGF-β receptor 2 (Tgfbr2) and the Eomes transcription factor (Tgfbr2 −/− Eomes −/− ) develop a severe autoimmune phenotype characterized by spontaneous germinal center (GC) formation, increased numbers of T follicular helper cells (T FH cells) and GC B cells, and autoantibody production.…”