CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
MetadataShow full item record
AbstractCD4(+) helper T cells orchestrate protective immunity against pathogens, yet can also induce undesired pathologies including allergies, transplant rejection and autoimmunity. Non-depleting CD4-specific antibodies such as clone YTS177.9 were found to promote long-lasting T cell tolerance in animal models. Thus, CD4 blockade could represent a promising therapeutic approach for human autoimmune diseases. However, the mechanisms underlying anti-CD4-induced tolerance are incompletely resolved. Particularly, multiple immune cells express CD4 including Foxp3(+) regulatory T cells (Tregs) and dendritic cells (DCs), both controlling the activation of CD4(+)Foxp3(-) helper T cells. Utilizing mixed leukocyte reactions (MLRs) reflecting physiological interactions between T cells and DCs, we report that anti-CD4 treatment inhibits CD4(+)Foxp3(-) T cell proliferation in an IL-2-independent fashion. Notably, YTS177.9 binding induces a rapid internalization of CD4 on both CD4(+)Foxp3(-) T cells and Foxp3(+) Tregs. However, no expansion or activation of immunosuppressive CD4(+)Foxp3(+) Tregs was observed following anti-CD4 treatment. Additionally, cytokine production, maturation and T cell priming capacity of DCs are not affected by anti-CD4 exposure. In line with these data, the selective ablation of Foxp3(+) Tregs from MLRs by the use of diphtheria toxin (DT)-treated bacterial artificial chromosome (BAC)-transgenic DEREG mice completely fails to abrogate the suppressive activity of multiple anti-CD4 antibodies. Instead, tolerization is associated with the defective expression of various co-stimulatory receptors including OX40 and CD30, suggesting altered signaling through the TCR complex. Consistent with our findings in mice, anti-CD4 treatment renders human CD4(+) T cells tolerant in the absence of Tregs. Thus, our results establish that anti-CD4 antibodies can directly tolerize pathogenic CD4(+)Foxp3(-) helper T cells. This has important implications for the treatment of human inflammatory diseases.
CitationCD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs. 2013, 47:73-82 J. Autoimmun.
JournalJournal of autoimmunity
The following license files are associated with this item:
- Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals.
- Authors: Mayer CT, Tian L, Hesse C, Kühl AA, Swallow M, Kruse F, Thiele M, Gershwin ME, Liston A, Sparwasser T
- Issue date: 2014 May
- Tolerogenic dendritic cells induce CD4+CD25hiFoxp3+ regulatory T cell differentiation from CD4+CD25-/loFoxp3- effector T cells.
- Authors: Huang H, Dawicki W, Zhang X, Town J, Gordon JR
- Issue date: 2010 Nov 1
- OX40 controls functionally different T cell subsets and their resistance to depletion therapy.
- Authors: Kroemer A, Xiao X, Vu MD, Gao W, Minamimura K, Chen M, Maki T, Li XC
- Issue date: 2007 Oct 15
- Dendritic cells support homeostatic expansion of Foxp3+ regulatory T cells in Foxp3.LuciDTR mice.
- Authors: Suffner J, Hochweller K, Kühnle MC, Li X, Kroczek RA, Garbi N, Hämmerling GJ
- Issue date: 2010 Feb 15
- Increased CD4+CD25+Foxp3+ regulatory T cells in tolerance induced by portal venous injection.
- Authors: He F, Chen Z, Xu S, Cai M, Wu M, Li H, Chen X
- Issue date: 2009 Jun