An approach to the immunophenotypic features of circulating CD4+NKG2D+ T cells in invasive cervical carcinoma

Abstract

BackgroundNKG2D, an activating immunoreceptor, is primarily restricted to NK cells and CD8+ T cells. The existence of an atypical cytotoxic CD4+NKG2D+ T cell population has also been found in patients with autoimmune dysfunctions. Nonetheless, contradictory evidence has categorized this population with a regulatory rather than cytotoxic role in other situations. These confounding data have led to the proposal that two distinct CD4+NKG2D+ T cell subsets might exist. The immune response elicited in cervical cancer has been characterized by apparent contradictions concerning the role that T cells, in particular T-helper cells, might be playing in the control of the tumor growth. Interestingly, we recently reported a substantial increase in the frequency of CD4+NKG2D+ T cells in patients with cervical intraepithelial neoplasia grade-1. However, whether this particular population is also found in patients with more advanced cervical lesions or whether they express a distinctive phenotype remains still to be clarified. In this urgent study, we focused our attention on the immunophenotypic characterization of CD4+NKG2D+ T cells in patients with well-established cervical carcinoma and revealed the existence of at least two separate CD4+NKG2D+ T cell subsets defined by the co-expression or absence of CD28.ResultsPatients with diagnosis of invasive cervical carcinoma were enrolled in the study. A group of healthy individuals was also included. Multicolor flow cytometry was used for exploration of TCR alpha/beta, CD28, CD158b, CD45RO, HLA-DR, CD161, and CD107a. A Luminex-based cytokine kit was used to quantify the levels of pro- and anti-inflammatory cytokines. We found an increased percentage of CD4+NKG2D+ T cells in patients with cervical cancer when compared with controls. Accordingly with an increase of CD4+NKG2D+ T cells, we found decreased CD28 expression. The activating or degranulation markers HLA-DR, CD161, and CD107a were heterogeneously expressed. The levels of IL-1beta, IL-2, TNF-alpha, and IL-10 were negatively correlated with the percentages of CD4+NKG2D+ T cells in patients with cervical carcinoma.ConclusionsTaken together, our results reveal the existence of two separate CD4+NKG2D+ T cell subsets defined by the co-expression or absence of CD28, the latter more likely to be present in patients with cervical cancer.

Primary EBV Infection Induces an Acute Wave of Activated Antigen-Specific Cytotoxic CD4+ T Cells

“…CD4-CTLs have to date been almost exclusively associated with late differentiated T EMRA CD4 + cells that accumulate during viral persistence. In this context, several cellular markers have been associated with the development or function of CD4-CTLs, including the transcription factors Eomes (17, 39, 40) and Hobit (11), the surface receptors NKG2D (41, 42) and CX 3 CR1 (17, 43), and the class I–restricted T cell–associated molecule CRTAM (44). We therefore asked whether these markers were similarly expressed by the EBV-specific CD4-CTLs induced by acute infection.…”

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

“…Cervical intraepithelial neoplasia, a premalignant abnormal growth preceding cervical cancer, is negatively associated with the presence of circulating cytotoxic CD4 T cells (101). Garcia-Chagollan et al identified a population of CD4+ CD28± NKG2D+ T-cells, which appear to be overrepresented in cervical cancer patients and which express the cytotoxic markers CD107a and CD161 (102). While the role of CD4 CTL in protection against tumor formation requires more directed study, the use of immunotherapy and vaccination to induce cytotoxic CD4 responses against tumor antigens is gaining interest, as discussed later in the review.…”

Viral Modulation of TLRs and Cytokines and the Related Immunotherapies for HPV-Associated Cancers

“…Another cytotoxic cell has also been encountered at high numbers in cervical cancer samples [ 109 ]. The expansion of this novel T cell subtype might affect lesion fate [ 110 ].…”

“…The expansion of this novel T cell subtype might affect lesion fate [ 110 ]. It is positive for CD4 and NKG2D markers and is subdivided in CD28 +/− , showing a statistically significant association with underexpression of several proinflammatory cytokines, such as IL1- β , IL-2, and TNF- α [ 109 ]. The role it plays and whether it is related to tumor growth or tumor suppression are still not known.…”