Adaptive human regulatory T cells: myth or reality? (original) (raw)
It is this complex, though highly relevant, problem that Akbar’s group addresses in their study in this issue of the JCI (14). Akbar, Vukmanovic-Stejic, and colleagues present data showing that the proportion and functional integrity of CD4+CD25hiFoxp3+ Tregs are maintained in older (>70 years) human subjects and that these cells most probably do not derive from the thymic lineage of CD4+CD25hiFoxp3+ Tregs.
The authors used an original method based on the in vivo incorporation of deuterium-labeled glucose (or glucose derivatives) into the DNA of dividing cells, with ultimate follow-up of the labeled population and subsequent evaluation of cell replication and survival within phenotypically distinct peripheral T cell subsets (14). The results obtained convincingly show that throughout the individual’s whole life span, lymphocytes corresponding to the phenotypic and in vitro functional definition of Tregs are generated from the peripheral pool of CD4+CD45RO+CD25–Foxp3– memory T cells (Figure 1).
T lymphocytes originate from the thymus. Evidence has been accumulated to demonstrate that “natural” Tregs, whose major function is to control autoimmune responses, stem as a separate lineage in the thymus. These natural Tregs are CD4+, they express the transcription factor Foxp3, which represents a lineage marker, and high levels of CD25. Natural Tregs that migrate to the periphery keep their phenotypic and functional properties, which are essentially cytokine independent. In parallel, other subsets of CD4+ Tregs have been described that very effectively control immune responses not only to self antigens but also to a wide variety of nonself antigens (microbial, tumoral, and transplantation antigens). These Tregs are not present as such in the thymus; they derive from peripheral precursors that are CD4+CD25– and differentiate into functional Tregs following adequate stimulation (in the presence of the cognate antigen and specialized immunoregulatory cytokines, i.e., TGF-β, IL-10, and IL-4). They are generally termed “adaptive” Tregs. Once differentiated, adaptive Tregs, like natural Tregs, may express CD25 and Foxp3. However, one main feature that differentiates adaptive from natural Tregs is their unique cytokine dependence. The study by Vukmanovic-Stejic et al. in this issue of the JCI (14) proposes that, in humans, even at a very advanced age, adaptive Tregs essentially emerge from CD4+CD25– T cells belonging to the memory T cell pool (previously primed by cognate antigens). Presently, one cannot exclude, however, that especially in young adults, some adaptive Tregs may emerge from naive, peripheral CD4+CD25– T cells. Tr1, Treg type 1.
The distinction between “natural” Tregs of thymic origin and “adaptive” Tregs exclusively generated from peripheral CD25– lymphocytes following adequate conditions (including antigen stimulation and cytokine milieu) was suggested a few years ago from data obtained and validated in the mouse. It was then shown that peripheral CD25– T cells whose T cell receptor or coreceptors (e.g., CD4) are stimulated in the presence of TGF-β acquire regulatory properties that may be assessed both in vitro and in vivo (2, 4, 15, 16).
The results reported here by Vukmanovic-Stejic et al. (14) may represent the first indication of a similar dichotomy in human Tregs. If confirmed, 2 other sets of data are of particular interest, namely those showing that human Tregs have a shorter doubling time when compared with other subsets studied (e.g., peripheral classical memory and naive-type T cells) and that they appear particularly sensitive to apoptosis. Such observations may present a solid argument for the dependence of human adaptive Tregs on continuous antigen stimulation and/or the presence of growth factors in their immediate environment for their differentiation and survival. This could turn out to be an essential condition of their homeostasis.