In vivo–activated CD103⁺ Foxp3⁺ Tregs: of men and mice

To the editor:

We read with interest the article by Zhao et al¹  on the specific abilities of murine CD103⁺ T regulatory (Treg) cells to ameliorate ongoing chronic graft-versus-host disease (cGVHD). The authors report here that only in vivo–activated effector/memory-like Tregs that express high amounts of the integrin αE (CD103) are able to efficiently control the disease in a murine model based on allogeneic transfer of DBA/2 donor cells into BALB/c hosts. In conclusion, the authors suggest that the infusion of human CD103⁺ Tregs might also ameliorate cGVHD in patients, so that the reported findings may offer a new strategy for the treatment of cGVHD patients.

In principle, the use of effector/memory-like Treg cells may be indeed beneficial also in human therapy. We would like to point out, however, that the markers for this Treg subset are not compatible between humans and mice. CD103 is a well-established marker for murine effector/memory-like Treg cells, which have been activated in vivo by antigen in a specific context. In naive mice, up to 30% of CD25⁺ FOXP3⁺ lymphocytes in fact express CD103.²  In contrast to this, cells with this marker are virtually absent among human CD25^high Foxp3⁺ Treg cells. It is expressed by less than 5% of human CD25^high Foxp3⁺ Treg cells in various tissues, including blood.^3,,–6  This applies also for β7, the integrin β-chain binding to CD103, which is only poorly expressed by human Treg cells.^3,7  Although in CD4⁺ T cells CD103 expression can be induced by different stimuli in vitro,^5,8  a significant expression of CD103 on human CD4⁺ cells with regulatory potential ex vivo was reported only in tonsils, here, however, mostly on CD25⁻ cells.⁵ 

Given the different expression of CD103 by Foxp3⁺ Tregs in mice and humans, it is highly questionable whether the results obtained with murine CD103⁺ Tregs can be translated 1:1 into a clinical setting. There is little doubt that equivalent cell subsets exist in humans and mice, and that effector/memory-like Treg cells fulfill analog functions in both species. Addressing these cells, however, requires considering species-specific differences. In humans, effector/memory-like Treg cells (T_REM) are better defined by markers such as CCR6 or CD39.^9,10