CD28 Controls Differentiation of Regulatory T Cells from Naive CD4 T Cells

Abstract

CD28 is required for the development of regulatory T cells (Tregs; CD4+CD25+Foxp3+) in the thymus and also contributes to their survival and homeostasis in the periphery. We studied whether and how CD28 and ICOS control the differentiation of Tregs from naive T cells. By using wild-type, CD28-, ICOS-, or CD28/ICOS-double knockout mice on C57BL/6 background as T cell sources, we found that CD28 is essential, whereas ICOS is dispensable, for the development and homeostasis of Tregs. Furthermore, the differentiation of Tregs from naive CD4+CD25− T cells in vivo also depends on CD28. The requirement of CD28 for Treg differentiation was mediated by IL-2, because neutralization of IL-2 with its specific mAb-blocked Treg differentiation from wild-type CD4+CD25− T cells and addition of IL-2 restored Treg differentiation from CD28−/− T cells. Other common γ-chain cytokines, IL-4, IL-7, or IL-15, do not share such a role with IL-2. Although CD28 is required for the differentiation of Tregs from naive T cells, already generated Tregs do not depend on CD28 to exert their suppressive function. Our study reveals a new aspect of CD28 function in regulating T cell response.

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…Consistent with our findings, CD28 has previously been shown to play a significant role in Treg cell generation and function (46,47). Indeed, T cells from CD28-deficient mice failed to generate inducible Treg cells, which was attributed to a lack of T cell IL-2 production.…”

Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling

“…13 The purity of CD4 ϩ CD25 Ϫ cells ranged from 85% to 95%, but that for CD4 ϩ CD25 ϩ cells was always less than 1% among total CD4 ϩ cells. CD4 ϩ CD25 Ϫ T cells were seeded at 2.5 ϫ 10 5 /well in 48-well plates and stimulated with 0.5-1.0 g/mL of anti-CD3 mAb in the presence of 1.25 ϫ 10 6 irradiated syngeneic T cell-depleted (TCD) splenocytes as antigen-presenting cells (APCs) with or without TGF-␤1.…”

“…4 Furthermore, CD28 costimulation is required for the generation of iTregs from naive CD4 ϩ CD25 Ϫ T cells through the production of IL-2. 13 However, there is also scattered evidence suggesting that high levels of CD28 costimulation reduce Foxp3 expression and limit iTreg generation through an undefined mechanism(s). 14,15 In this study, we clearly demonstrate that the high levels of CD28 costimulation suppress generation of iTregs from naive CD4 T cells while promoting the expansion of Teffs.…”

Immunological Considerations for Inducing Skin Graft Tolerance

“…We now accept the description of the predominant category of regulatory cells responsible for allograft survival, the generation of chimerism and mixed chimerism, protection from autoimmunity and reduced risk of graft vs. host disease (GVHD) and host vs. graft disease (HVG) as being CD4 + CD25 + Foxp3 + regulatory T lymphocytes. These Tregs may be naturally occurring in the thymus or adaptively induced in response to foreign antigen and costimulation blockade (Guo et al, 2008, Schwartz, 2005, Sakaguchi, 2005, Coenen et al, 2005, von Boehmer, 2005. The Tregs express the forkhead transcription factor Foxp3 (Fontenot and Rudensky, 2005), and there is some evidence that the expression level of this transcription factor may be a key indicator of the level of immunosuppression potential (Chauhan et al, 2009) The immunosuppressive effect of these cells has been shown by in vivo and in vitro experiments.…”