CD4⁺CD25^hi regulatory T‐cell frequency correlates with persistence of human papillomavirus type 16 and T helper cell responses in patients with cervical intraepithelial neoplasia

Abstract

CD4 1 CD25 hi CTLA4 1 FoxP3 1 regulatory T cells (Treg) have been shown to maintain immune tolerance against self antigens and increased circulating frequencies have been reported in various types of cancers. Circulating invariant natural killer T-cells (iNKT) are reduced in cancer patients and low iNKT frequency is related to poor prognosis. It is not yet clear whether high Treg numbers and low iNKT cell numbers pose an increased risk for the progression of premalignant lesions or whether Treg and iNKT cell numbers are influenced by dysplasia. We therefore studied prospectively the relation between iNKT cell and Treg frequencies and the natural course of human papillomavirus type 16 (HPV16) induced pre-malignant cervical dysplasia in 82 patients who participated in a nonintervention cohort study of women with abnormal cytology. Treg frequencies were significantly increased in women who had persistent HPV16 infection. Within the HPV16 persistence group there was no difference in Treg frequencies among patients who developed a CIN3 lesion and patients who did not progress to CIN3. Furthermore, Treg frequencies were increased in patients who had detectable HPV16 E7 specific IL-2 producing T-helper cells, which suggests a causal role of HPV infection in Treg development in parallel with HPV16 specific T helper cells. No evidence was found for a role for iNKT cells in persistence of HPV16 and progression of HPV16 induced CIN lesions. However, HPV-persistence-associated Tregs may explain the inefficacy of concomitant persistence associated immunity and may contribute to subsequent progression to neoplasia. ' 2007 Wiley-Liss, Inc.Key words: regulatory T cells; invariant NKT cells; HPV type 16; persistence; CIN Specific immune responses against viruses and cancer are controlled by various regulatory cells. This negative regulation occurs by naturally occurring CD4 1 CD25 hi regulatory T cells (Tregs), induced antigen specific regulatory T-cells (Tr1 and TH3 cells) or CD4 1 CD25 hi cells developing from CD4 1 CD25 2 T-cells. Unlike naturally occurring Tregs, which can be identified by intracellular cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and forkhead box (Fox)P3 expression, antigen specific regulatory T-cells have no discriminating phenotype. 1-3 Increased numbers of circulating Tregs have been detected in patients with solid tumors 4 and hematologic malignancies. 5 While there is evidence for an influence of tumor associated factors, 6 it has also been suggested that an age related increase in Treg frequencies is associated with an increased risk to develop cancer. 7 Another regulatory T cell is the invariant natural killer T (iNKT) cell, which is characterized by expression of the Va24Vb11 invariant T-cell receptor and NK cell receptors. iNKT cells have the capacity to either enhance or suppress immuneresponses by secreting proinflammatory or anti-inflammatory cytokines respectively upon activation via antigenic recognition of the glycolipid a-galactosylceramide (a-GalCer) in the context of the non-polymo...

Correlation of CXCL12 Expression and FoxP3+ Cell Infiltration with Human Papillomavirus Infection and Clinicopathological Progression of Cervical Cancer

“…18,29 A direct relationship between the HPV infection and the onset of an immune suppressive environment has been suggested by a prospective study of HPV16-related lesions, in which regulatory T cell frequencies were significantly increased in women who had persistent HPV16 infection and HPV16-specific interleukin-2 producing T-helper cells. 19 Furthermore, it has also been observed that, in patients with HPV6-and HPV11- …”

“…In contrast, high levels of CXCL12 expression result in reduced infiltration of the tumor by tumor antigen-specific T cells 17 and the suppression of antitumor immune responses via various mechanisms including the intratumoral accumulation of FoxP3 ϩ suppressor T cells. 18,19 We hypothesized that secretion of CXCL12 by cervical tumors is correlated with progression of the tumor and loss of immune control. To explore this hypothesis we first examined whether clinicopathological progression of cervical cancer is associated with an increase in CXCL12 expression and a concomitant reduction in immune cell infiltration into the tumor as the tumor progresses from a preinvasive to an invasive state.…”

Cytokines and Markers of Immune Response to HPV Infection

“…One research group has made extensive use of their study population to characterize several aspects of immune response as measured in PBMCs (de Gruijl, Bontkes et al 1998;Bontkes, de Gruijl et al 1999;de Gruijl, Bontkes et al 1999;Bontkes, de Gruijl et al 2000;Molling, de Gruijl et al 2007). However, few studies have been so thorough.…”

“…al. (Molling, de Gruijl et al 2007) evaluated cultured PBMCs again stimulated with 14 different 20mer HPV16 E7 peptides or with PHA and measured both IL-2 levels and CTL activity. Importantly, they also measured invariant natural killer T-cells (iNKT) and FoxP3+ regulatory T cells (Tregs) levels by flow cytometry (FACSCalibur).…”

Recent advances in strategies for immunotherapy of human papillomavirus‐induced lesions

“…41 Moreover, cervical lesions in patients with HPV161 or HPV181 tumors are highly infiltrated with CD4 1 FoxP3 1 T cells whereas they are mostly absent in the normal cervix. 42 This suggests that amongst the population of tumor-infiltrating lymphocytes, there is a significant population that can suppress antitumor immune responses within the tumor itself if the endogenous or vaccine-induced CTL response to HPV antigens is not great enough.…”