Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells

Abstract

Despite thymic deletion of cells with specificity for self-antigens, autoreactive T cells are readily detectable in the normal T-cell repertoire. In recent years, a population of CD4(+) T cells that constitutively express the interleukin-2 receptor-alpha chain, CD25, has been shown to play a pivotal role in the maintenance of self-tolerance in rodent models. This study investigated whether such a regulatory population exists in humans. A population of CD4(+)CD25(+) T cells, taken from the peripheral blood of healthy individuals and phenotypically distinct from recently activated CD4(+) T cells, was characterized. These cells were hyporesponsive to conventional T-cell stimuli and capable of suppressing the responses of CD4(+)CD25(-) T cells in vitro. Addition of exogenous interleukin-2 abrogated the hyporesponsiveness and suppressive effects of CD4(+)CD25(+) cells. Suppression required cell-to-cell contact but did not appear to be via the inhibition of antigen-presenting cells. In addition, there were marked changes in the expression of Notch pathway molecules and their downstream signaling products at the transcriptional level, specifically in CD4(+)CD25(+) cells, suggesting that this family of molecules plays a role in the regulatory function of CD4(+)CD25(+) cells. Cells with similar phenotype and function were detected in umbilical venous blood from healthy newborn infants. These results suggest that CD4(+)CD25(+) cells represent a population of regulatory T cells that arise during fetal life. Comparison with rodent CD4(+)CD25(+) cells suggests that this population may play a key role in the prevention of autoimmune diseases in humans.

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

“…This subset of cells has been found in human solid tumors, tumor ascites fluids and hematological malignancies [32][33][34], and their presence correlated in human ovarian cancer with a poor prognosis [32,33]. Indirect evidence suggests that Tregs are able to suppress tumor-specific immunity [34][35][36][37][38][39][40][41][42], but definitive evidence of the role of this T cell subset in the immunopathogenesis of human cancer is still lacking.…”

Quantification of the chemokines CCL17 and CCL22 in human colorectal adenocarcinomas

“…The chemokines CCL17 and CCL22 attract CCR4-bearing cells, in particular Th2-type cells (19)(20)(21) and regulatory Tregs (22,23). Recent studies have revealed the participation of the CCL17 and CCL22 proteins in diseases such as atopic dermatitis (30) and lymphoma (31).…”

“…Since CCL17 and CCL22 signal through CCR4, they can act as chemoattractants for Th2 CD4 + T-cell-mediated immunity (19)(20)(21). CCR4 is also expressed on Tregs, which play an important role in maintaining immune balance and have been detected in the peripheral blood of humans (22,23). Tregs are known to be a potent inhibitor of the antitumour immune response (32).…”

“…It has been suggested that CCR4 is especially polarised to Th2-type cells (19)(20)(21) and that these cells produce anti-inflammatory cytokines such as IL-4, IL-5, IL-10 and IL-13 (20,21). CCR4 is also expressed on regulatory T cells (Treg), which play an important role in maintaining immune balance and have been detected in peripheral blood from humans (22,23).…”

“…It has been suggested that CCR4 is especially polarised to Th2-type cells (19)(20)(21) and that these cells produce anti-inflammatory cytokines such as IL-4, IL-5, 21). CCR4 is also expressed on regulatory T cells (Treg), which play an important role in maintaining immune balance and have been detected in peripheral blood from humans (22,23).Another ligand for CCR4 is CCL22, also named MDC (macrophage-derived chemokine), which is expressed in macrophages, dendritic cells, B cells, intestinal epithelial cells and colon tissue, and thereby serves to recruit CCR4-expressing cells (16,18,19,24,25). A study has shown that CCL22, but not CCL17, mRNA was elevated in colon cancer tissues compared to non-neoplastic colon tissues, and that CCR4 transcripts were weakly detected in some colon cancer tissues (26).…”