Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo

Abstract

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

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection

“…Treg cells are classified into two T cells [5][6][7]. Treg cells target effector T cells and dendritic cells (DCs) by modulating their maturation and function through several mechanisms that suppress immune responses [8][9][10]; these include secretion of inhibitory cytokines (IL-10, IL-35, and TGF-β), granzyme/perforin-dependent mediated cytolysis, metabolic disruption [11][12][13][14][15], and the expression of LAG3 and CTLA4, which alter DC function [16,17].…”

p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation

“…58 Furthermore, treatment with adoptive T-cell transfer can result in synergistic anti-neoplastic effects owing to the increased immunogenicity of cancer cells. 59 Yet, for all these antitumor effects, there appears to be a balance between anti-and pro-tumor effects by both CD4 þ and CD8 þ T cells, [60][61][62] and regulatory T cells can migrate into the microenvironment and suppress antitumor responses in human ovarian carcinoma. 63 Considering the variable effects of this multitude of stromal cell and immune response interactions, the mechanism by which p53 deficiency in MSCs affects T-cell function in tumors warrants further exploration.…”

Immunosenescent colitogenic CD4+ T cells convert to regulatory cells and suppress colitis

“…A recent publication by Vukmanovic-Stejic and colleagues [21] demonstrated that a substantial proportion of peripheral human CD4 + CD25 high Foxp3 + Treg cells is generated from rapidly dividing, highly differentiated CD4 + memory T cells in addition to the cells of same phenotype derived from the thymus. Moreover, Liu and colleagues [34] reported that the interaction between neurons and CD4 + T cells results in the conversion of encephalogenic CD4 + T cells to CD4 + CD25 + Foxp3 + T R cells in a murine model of experimental autoimmune encephalomyelitis (EAE).…”

“…Vukmanvic-Stejic and colleagues [21] have recently reported that a proportion of peripheral CD4 + CD25 high Foxp3 + Treg cells in humans are generated from rapidly dividing memory CD4 + CD45RO + T cells in addition to thymus-derived classical CD4 + CD25 high Foxp3 + Treg cells. Furthermore, colitogenic CD4 + T cells in this colitis model proliferate and expand in response to foreign antigens more rapidly in immunodeficient SCID mice than do slow-dividing antigen-specific 'true' memory T cells [17].…”