While memory T cells are maintained by continuous turnover, it is not clear how human regulatory CD4 + CD45RO + CD25 hi Foxp3 + T lymphocyte populations persist throughout life. We therefore used deuterium labeling of cycling cells in vivo to determine whether these cells could be replenished by proliferation. We found that CD4 + CD45RO + Foxp3 + CD25 hi T lymphocytes were highly proliferative, with a doubling time of 8 days, compared with memory CD4 + CD45RO + Foxp3 -CD25 -(24 days) or naive CD4 + CD45RA + Foxp3 -CD25 -populations (199 days). However, the regulatory population was susceptible to apoptosis and had critically short telomeres and low telomerase activity. It was therefore unlikely to be self regenerating. These data are consistent with continuous production from another population source. We found extremely close TCR clonal homology between regulatory and memory CD4 + T cells. Furthermore, antigen-related expansions within certain TCR Vb families were associated with parallel numerical increases of CD4 + CD45RO + CD25 hi Foxp3 + Tregs with the same Vb usage. It is therefore unlikely that all human CD4 + CD25 + Foxp3 + Tregs are generated as a separate functional lineage in the thymus. Instead, our data suggest that a proportion of this regulatory population is generated from rapidly dividing, highly differentiated memory CD4 + T cells; this has considerable implications for the therapeutic manipulation of these cells in vivo. IntroductionBoth memory and regulatory populations of T cells must be maintained in tandem in order to generate controlled immunity for the lifetime of the organism. Since the thymus involutes early in life, memory T cells have to largely be maintained by lifelong turnover of preexisting populations of specific T cells in adults (1, 2). The corollary of this is that thymic involution during aging will also severely restrict the production of Tregs by this organ. The source of these cells in adult humans and the relative contributions of long-term survival and ongoing turnover to the maintenance of CD4 + CD25 hi Foxp3 + Treg populations remain unknown.The naturally occurring CD4 + CD25 hi Treg subset that expresses the lineage marker Foxp3 represents an important population of suppressive T cells that can prevent reactivity to both self and nonself antigens (3-5). These cells also downregulate immune responses as pathogen is cleared (3)(4)(5). Early studies demonstrated that in mice, CD4 + CD25 hi Tregs are generated as a distinct population in the thymus (6). Indeed, in mice, there is substantial overlap of TCR repertoires between thymic and peripheral CD4 + Foxp3 + Tregs, suggesting that the thymic regulatory pool makes a significant contribution to the peripheral regulatory cells (7). However, murine CD4 + CD25 hi Tregs, which are phenotypically and functionally identical to the thymus-derived population can also be

Material

CD4+CD25+ T cells in patients with AD have normal suppressive activity compared with healthy controls. Tregs and tacrolimus have additive effects on the inhibition of proliferation in response to PPD and Der p1.

SUMMARYWe investigated the expression of T helper (Th)1/Th2 regulatory cytokine receptors on lymphocytes from patients with common variable immunodeficiency (CVID), a disorder associated with raised Th1 cytokine production, comparing the results with those from healthy individuals and atopic asthmatics, the latter generally considered to have a Th2-driven disease. We proposed that alterations in some of the relevant receptors might be related to the observed imbalances in Th1/Th2 cytokines. Cells from CVID patients showed an increase in the percentages of CD212 [interleukin (IL)-12R β 1] cells within the CD4 + CD45RA + and CD8 + CD45RA + subsets (24% and 41%, respectively), as compared to CD4 + CD45RA + and CD8 + CD45RA + in healthy subjects (6% and 23%, respectivey). Approximately 21% of the CD4 + CD45RA + naïve cells expressed IL-18R α , compared with 11% in healthy subjects. In contrast, the cytokine-receptor expression in asthmatics was similar to that of controls. In spite of the above differences, after 72 h of stimulation with anti-CD3 and anti-CD28, cytokine receptor up-regulation was similar in all three groups, with up to 80% of both CD45RA + and CD45RO + lymphocytes expressing CD212 (IL-12R β 1) and IL-18R α . Approximately 50% of the 'naïve', and 25% of the 'memory' subpopulations up-regulated IL-12R β 2. These findings provide further evidence of a polarization towards a Th1 immune response in CVID, the mechanism possibly involving up-regulation of IL-12-mediated pathways.

SUMMARYThe objective of this study was to demonstrate the variable expression of cytokine receptors on naive versus memory human CD4+ T cell subpopulations in tonsillar tissue, cord blood and adult blood. We prove that the receptors for both interleukin (IL)-12 and IL-18 are expressed exclusively on memory T cells. This observation was seen not only on the CD45RO + memory T cells but also on a significant percentage of the CD45RA-, CD27 -and CCR7 -populations. Furthermore, CD45RA+ or CCR7 + CD4 + T cells that expressed IL-12R b 1 and IL-18R a did not express CD31, a marker for recent thymic emigrants. We reveal that cord blood lymphocytes do not express IL-12R b 1 whereas IL-18R a expression was detected at low levels. Importantly, the IL-12R b 2 signalling chain, which is absent in all resting T cells, was up-regulated in both CD45RA+ and CD45RO + T cells as a result of stimulation with anti-CD3 and anti-CD28 in vitro . This observed up-regulation was, however, restricted to 80% of the total CD4 + population. Finally, a very small proportion of the CD4 + CD45RO + tonsillar T cells expressed the IL-12 and IL-18 receptors, thereby establishing the differential expression of these receptors between peripheral and tonsillar memory T cell subpopulations.