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Advances on Non-CD4 + Foxp3+ T Regulatory Cells: CD8+, Type 1, and Double Negative T Regulatory Cells in Organ Transplantation

Ligocki, Ann J. PhD1; Niederkorn, Jerry Y. PhD1

doi: 10.1097/TP.0000000000000813

The overwhelming body of research on T regulatory cells (Treg) has focused on CD4 + CD25 + Foxp3+ T cells. However, recent years have witnessed a resurgence in interest in CD4 − CD8+, CD4 − CD8− (double negative [DN]), and CD4 + Foxp3− type 1 Treg (Tr1) Treg and their role in controlling autoimmune diseases and in promoting the survival of organ allografts and xenografts. CD8+ and DN Treg can arise spontaneously (natural Treg) or can be induced in situ. Both CD8+ and DN Treg have been shown to enhance the survival of organ allografts and xenografts. Additionally, both can suppress alloimmune responses by contact-dependent mechanisms by either inducing apoptosis or mediating direct cytolysis of effector T cells. CD8+, DN, and Tr1 Treg can also act in a contact-independent manner by elaborating soluble immunosuppressive factors, such as TGF-β and IL-10. Applying CD8+, DN, and Tr1 Treg for enhancing the survival of organ allografts and xenografts is still in its infancy but holds significant potential. Furthermore, there is a need for a more comprehensive understanding of how current immunosuppressive therapies applied to organ transplantations affect the wide array of Treg populations.

Ligocki and Niederkorn provide a timely review on the role of non-canonical FoxP3-negative regulatory T cells. Defining the role of these cells in transplantation is at its infancy but tantalizing data suggest that these cells may have significant therapeutic potential.

1 Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.

Received 2 January 2015. Revision requested 6 April 2015.

Accepted 20 April 2015.

Funding: Supported by NIH grants EY007641, EY005631, and EY020799 and Research to Prevent Blindness.

The authors declare no conflicts of interest.

A.J.L. and J.Y.N. contributed to the writing of the article.

Correspondence: Jerry Y. Niederkorn, Department of Ophthalmology, U.T. Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9057. (

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