CD4⁺CD25⁺ T cells: friends or foes?

Like the mythical Hydra that grew new heads after being apparently successfully decapitated, the concept of the suppressor T cell never quite goes away, re-emerging at intervals—currently as the regulatory T (T_reg) cell. Questions regarding the nature of such cells persist. One such population, the CD4⁺CD25⁺ thymic-derived T_reg cells, is critical to the maintenance of self-tolerance and prevention of autoimmunity in mice.¹  These cells also play a role in murine graft-versus-host disease (GVHD), since their depletion prior to transplantation increases GVHD, while adoptive transfer of these cells mitigates GVHD lethality.²  CD4⁺CD25⁺ T_reg cells have been recently reported in human peripheral blood and thymus, but their clinical significance has yet to be clarified. In their paper, Stanzani and colleagues (page 1140) sought to determine whether the relationship between donor CD4⁺CD25⁺ T_reg cells and GVHD severity, seen in murine transplantation, would hold up in humans.

To this end, the content of CD25⁺ T cells was analyzed in donor grafts from a random cohort of 60 HLA-matched sibling peripheral blood stem cell transplantations performed at the M. D. Anderson Cancer Center. The study reached the unexpected conclusion that higher numbers of donor CD4⁺CD25⁺ cells correlate with more clinical GVHD (acute and chronic). Furthermore, the same association was seen for CD8⁺CD25⁺ cells. To explain this paradoxical outcome, the authors rightly point out that circulating human interleukin-2 receptor α-chain (IL-2Rα, CD25)–expressing T cells represent a heterogeneous population, containing not only regulatory but also activated effector T cells. Unfortunately, no definitive phenotypic markers can absolutely discriminate between the 2 functional subsets. The authors conclude that the “activation state” of donor T cells prior to transplantation may be an important risk factor for the development of GVHD.

So why did the frequency of activated T cells in the allograft correlate with GVHD? It is unlikely that these cells represent minor histocompatibility antigen–specific T cells facilitating the initiation of GVHD. It is possible, as the authors suggest, that activated T cells amplify the alloresponse through participation in the effector phase of GVHD. A third possibility is that higher CD25⁺ expression is simply a marker for increased donor immune responsiveness. At any given frequency of host-reactive T cells, there appears to be considerable person-to-person variation in the strength of the alloresponse. In support of this is the poor correlation between T-cell precursor frequency assays (both helper and cytotoxic) and clinical GVHD.³  This variation presumably reflects differences in expression of a large number of immune response genes. One clear example of this is the relationship among cytokine gene polymorphisms, cytokine expression, and clinical GVHD.^4,5  Further studies, in both mouse transplantation models and in human transplant recipients, will be needed to test these possibilities.

The clinical importance of T_reg cells in allogeneic transplantation should become clearer with better definition of the biology and phenotype of these cells. Recent discoveries of underlying molecular mechanisms (eg, Foxp3 as a critical regulator of T_reg cell development and function) are a start.