Follicular lymphoma B cells induce the conversion of conventional CD4⁺ T cells to T‐regulatory cells

Abstract

There has been accumulating evidence that CD4 1 CD25 1 FoxP3 expressing regulatory T cells (Treg) are highly concentrated in tumors, thereby fostering an immune-privileged microenvironment. Some studies have shown that T-cell receptor (TCR) stimulation can convert conventional T cells into Treg. Follicular lymphoma (FL) B cells can enhance this Treg conversion. We investigated whether FL tumor B cells, as opposed to normal B cells, are unique in their ability to convert effector T cells into Treg. We found that tumor B cells alone, without artificial TCR stimulation, could induce conventional T cells to express FoxP3 and to acquire regulatory function. In contrast to their malignant counterpart, normal B cells did not induce Treg conversion. Treg conversion was independent of the T cell background, as T cells isolated from FL or normal peripheral blood were equally susceptible to being converted by tumor B cells. Our study provides evidence for a tumor-specific mechanism by which FL tumor cells promote immune escape through the induction of Treg. ' 2008 Wiley-Liss, Inc.Key words: tumor microenvironment; immune escape Tumors induce immunologic tolerance by several mechanisms, involving tolerogenic antigen presenting cells, Foxp3 1 CD4 1 CD25 1 regulatory T cells (Treg) and soluble immunoregulatory factors. 1-4 An increased frequency of Treg was first observed in the peripheral blood of patients with bronchial carcinoma when compared with healthy individuals. 5 Then similar findings were reported in patients with a variety of cancer types. This was followed by several reports indicating that Treg can be actively recruited and expanded in the tumor microenvironment. 4,[6][7][8][9] Treg that are found within the tumor microenvironment are highly suppressive and abrogate effector function of cytotoxic T cells as well as NK cell-mediated cytotoxicity. 1,7,[10][11][12][13] These data have important clinical implications, as targeting Treg cells can enhance therapeutic antitumor effect in both humans and animal models. [14][15][16][17][18] Interestingly, depletion of Treg cells led to crossreactive tumor immunity against tumors of diverse origins. 19 Factors that have been described to be important for Treg induction within the tumor include TGF-b, IL-10, H-Ferritin, IDO and Prostaglandin E 2 (PGE 2 ). 9,20-22 These findings highlight the importance of understanding the mechanisms of immune-escape in the tumor microenvironment.Stimulation of the T-cell receptor (TCR) or priming with dendritic cells can induce FoxP3 expression and the acquisition of Treg activity in CD4 1 CD25 2 T cells from normal PBMC. [23][24][25] Yang et al. extended these findings and demonstrated that tumor infiltrating T cells in follicular lymphoma (FL) -involved lymph nodes could also be induced to express FoxP3 through TCR stimulation. Furthermore, they showed that CD701 malignant B cells could facilitate this conversion of conventional T cells to Treg in FL. 26 In this study, we investigated whether Treg induction in FL is a tumor-specific phe...

Pathogenesis of follicular lymphoma

“…It was also recently shown that IL-12 secretion by malignant B cells induces T cell exhaustion via expression of TIM3 (87). Moreover, FL cells induce the conversion of effector T cells into FOXP3-expressing Tregs, which suppress the proliferation and activity of both CD4 + CD25 -and CD8 + T cells (88)(89)(90). Taken together, these observations illustrate how the malignant B cells dampen the function of various T cell subsets in the FL microenvironment in order to escape immunosurveillance.…”

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis

“…71 Moreover, FL cells induce the conversion of effector T cells into FOXP3-expressing Tregs, which suppresses the proliferation and activity of both CD4 + CD25 -and CD8 + T cells. 38,78,79 In conclusion, these observation illustrate how malignant B cells disable the function of various T-cell subsets in the FL microenvironment to escape immune surveillance.…”

Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell–mediated immunosurveillance in follicular lymphoma

“…FL cells themselves can induce a regulatory phenotype on conventional T cells in situ. 24,25 This effect could potentially enhance peripheral tolerance to shared and individual idiotype epitopes. Therefore, the efficacy of idiotype-directed T-cell immunity presumably depends on the balance between the immunogenicity of individual idiotype epitopes and on the extent of regulatory T-cell activity in the local immune environment.…”