In vivo peripheral expansion of naive CD4+CD25highFoxP3+ regulatory T cells in patients with multiple myeloma

Abstract

IntroductionThe lack of clinically sufficient antitumor immune responses has been attributed to soluble inhibitory factors such as TGF␤1 1,2 or PGE 2 3-5 as well as the induction and expansion of regulatory cells. 6,7 CD4 ϩ CD25 high regulatory T cells (T reg cells) were shown to be expanded in murine tumor models. 8 Moreover, their deletion reinstated an efficient antitumor immune response leading to complete tumor regression. [9][10][11] We and others have demonstrated that CD4 ϩ CD25 high FoxP3 ϩ T reg cells are also expanded in patients with solid tumors, [12][13][14][15][16][17][18][19] Hodgkin lymphoma, 20,21 or B-cell chronic lymphocytic leukemia (CLL). 22 Both in humans and in animal models, T reg cells have been described as anergic cells exerting strong suppression after T-cell receptor (TCR) stimulation. [23][24][25] As demonstrated in murine models, natural T reg cells usually originate from the thymus, 26,27 although cells with similar characteristics can also be generated in the periphery under appropriate conditions. 28 More recently, the diversity and developmental stage of thymic emigrants with a T reg -cell phenotype as well as CD4 ϩ CD25 ϩ T reg cells within peripheral blood were examined. 29,30 In healthy individuals, the levels of T-cell receptor excision circles (TRECs) were comparable in both conventional CD4 ϩ CD25 Ϫ and regulatory CD4 ϩ CD25 ϩ thymic populations. However, the number of TRECs was significantly higher in thymic emigrants than in peripheral blood-derived T cells, which strongly suggests thymic development of human CD4 ϩ CD25 high T reg cells. 30 Nevertheless, conventional CD4 ϩ CD25 Ϫ T cells from peripheral blood of healthy donors contained higher TREC numbers than their CD4 ϩ CD25 ϩ counterparts, which is in line with the possibility of extrathymic expansion particularly within the T reg -cell subset. 29 Until recently, CD4 ϩ CD25 high T reg cells have been described to belong to the memory T-cell compartment. 24,[31][32][33] Valmori et al, 34 however, identified a T reg -cell population with a naive phenotype (CCR7 ϩ CD45RA ϩ ), which they termed natural naive T reg cells (NnTregs). As expected, the frequency of these NnTregs was relatively low in healthy individuals. NnTregs were shown to vigorously proliferate in response to contact with autologous antigen-presenting cells, suggesting that particularly this subpopulation is enriched in T cells bearing self-reactive T-cell receptors. 34 Most recently, Seddiki et al 35 described the persistence of a population of naive CD45RA ϩ T reg cells in adult life.Little is known about the differentiation, origin, and mechanisms of expansion of T reg cells in cancer patients. We and others have observed that increase of T reg -cell frequency correlates with disease state, 13,22 which might be explained by an antigendependent mechanism of peripheral expansion in response to tumor progression. However, it is unknown if these T reg cells are also more differentiated toward a central or even effector memory phenotype. M.B. designed res...

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

“…Initially, a decrease in Treg numbers was reported in MM patients, along with a defect in their ability to suppress T-cell proliferation [57]. In contrast, several more recent studies have concluded that the number of functionally intact Treg is increased in MM patients [49,50,[58][59][60]. These observations are in accordance with observations made in several other malignancies [56], and suggest that MM cells evade immune surveillance partially through the increase of suppressive Tregs [60].…”

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

“…First, the lack of a specific marker for Treg has led to the assumption that only CD4ϩ,CD25 high T cells represent human Treg. (25,(38)(39)(40). However, it is unclear whether the reported reduction in the number of CD4ϩ,CD25 high Treg in SLE is compensated by an increase in the number of CD25 low ,Foxp3ϩ Treg that was not analyzed in previous studies.…”

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4+CD25– cells

“…Since both Foxp3 isoforms appear to possess similar functions but their mRNA expression levels show no fixed ratio at the PBMC level, it seems important to determine total Foxp3 mRNA levels rather than quantifying the mRNA of only one of the isoforms. Fortunately, until now several studies have used PCR primer sets that amplify both Foxp3FL and Foxp3DE2 isoforms [25][26][27][28][29][30]. Nonetheless, interpretation of several other studies may be difficult since either the amplified Foxp3 region was not exactly reported [31][32][33][34] or only the full-length Foxp3 mRNA was amplified without any reasoning [35].…”