Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Sheu, Bor‐Ching; Lin, Rong‐Hwa; Lien, Huang-Chun; Ho, Hong Nerng; Hsu, Su-Ming; Huang, Su‐Cheng

doi:10.4049/jimmunol.167.5.2972

Cited by 181 publications

(125 citation statements)

References 51 publications

(48 reference statements)

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“…Patient studies show an expansion of TC2 populations in various disease conditions including cancer (39)(40)(41) and chronic viral infections (27,42). In all of these cases, TC2 accumulation was associated with disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Banchereau

Zurawski

Thompson-Snipes

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Human Langerhans cells (LCs) are highly efficient at priming cytolytic CD8 + T cells compared with dermal CD14 + dendritic cells (DCs). Here we show that dermal CD14 + DCs instead prime a fraction of naïve CD8 + T cells into cells sharing the properties of type 2 cytokinesecreting CD8 + T cells (TC2). Differential expression of the CD8-antagonist receptors on dermal CD14 + DCs, the Ig-like transcript (ILT) inhibitory receptors, explains the difference between the two types of DCs. Inhibition of CD8 function on LCs inhibited cytotoxic T lymphocytes (CTLs) and enhanced TC2 generation. In addition, blocking ILT2 or ILT4 on dermal CD14 + DCs enhanced the generation of CTLs and inhibited TC2 cytokine production. Lastly, addition of soluble ILT2 and ILT4 receptors inhibited CTL priming by LCs. Thus, ILT receptor expression explains the polarization of CD8 + T-cell responses by LCs vs. dermal CD14 + DCs.D endritic cells (DCs) are potent antigen-presenting cells (APCs) responsible for inducing Ag-specific immunity and tolerance (1). Several populations of DCs take up residence in different tissues and carry common as well as unique biological functions (2, 3). The healthy human skin displays at least three DC populationsLangerhans cells (LCs) in the epidermis and interstitial CD1a + and CD14 + DCs in the dermis (4, 5). Each of the different skin DC subsets carries out specialized functions. CD14 + DCs that reside in the dermis are particularly efficient at controlling the differentiation of naïve B cells into plasma cells (6, 7). Epidermal LCs, conversely, are highly efficient at priming naïve CD8 + T cells into potent cytotoxic T lymphocytes (CTLs). Both DC subsets are equally efficient at inducing a secondary CD8 + T-cell response (7-9).T lymphocytes are also composed of subsets. The CD4 + T-cell subsets, Th1 and Th2 (10), were the first to be characterized. Subsequently, other subsets have been identified and include Tregs, Th17, Tfh, and Th9 (11). CD8 + T-cell subsets have also been divided into subsets based on their cytokine production profile (12)(13)(14). Type 1 cytokine-producing T cells (TC1) express IFN-γ and TNF-α, whereas type 2 cytokine-producing T cells (TC2) produce IL-4, -5, and -13. Suppressor CD8 + T cells produce IL-10 and TGF-β and are characterized by low expression levels of CD8 and CD28 (15,16). These findings are physiologically relevant because the balance between TC1 to TC2 and CD8 + suppressor T cell populations correlates with a patient's ability to overcome tumor overgrowth or viral infections.Studies with CD8-α or CD8-β gene-targeted mice have revealed that CD8 plays a key role in the maturation and function of MHC class I-restricted T lymphocytes (17,18). Interacting with MHC in the immunological synapse, a specialized junction between a T lymphocyte and an APC, CD8 can enhance the affinity of T-cell receptor (TCR)-CD8 complexes for MHC-peptide (pMHC) complexes by ∼10-fold (19). The importance of CD8 is also demonstrated by the function of two inhibitory receptors, ILT2 and ILT4, that can...

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Section: Discussionmentioning

confidence: 99%

Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Banchereau

Zurawski

Thompson-Snipes

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…This shift from a Th1-to a Th2-type response also contributes to the decreased activity of effector CTLs. 36 Another important reason for the failure of tumor immune surveillance is the augmentation of immunosuppressive Treg cells. 37 In accordance with previous findings, our results depicted a reduction in the number of effector and memory T cells and a shift from a Th1-to a Th2-type response in tumor-bearing hosts, along with elevated levels of Treg cells.…”

Section: Discussionmentioning

confidence: 99%

Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts

et al. 2010

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Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion. CD8 1 cytotoxic T lymphocytes (CTLs) are involved in antigen-specific tumor destruction and CD4 1 T cells are essential for helping this CD8 1 T cell-dependent tumor eradication. Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells. Curcumin has previously been shown to have antitumor activity and some research has addressed the immunoprotective potential of this plant-derived polyphenol in tumor-bearing hosts. Here we examined the role of curcumin in the prevention of tumor-induced dysfunction of T cell-based immune responses. We observed severe loss of both effector and memory T-cell populations, downregulation of type 1 and upregulation of type 2 immune responses and decreased proliferation of effector T cells in the presence of tumors. Curcumin, in turn, prevented this loss of T cells, expanded central memory T cell (T CM )/effector memory T cell (T EM ) populations, reversed the type 2 immune bias and attenuated the tumor-induced inhibition of T-cell proliferation in tumor-bearing hosts. Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-b and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-b and IL-10 in these cells. More importantly, curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.

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“…TILs and PBLs were isolated by methods described in our previous study. [18][19][20][21][22] Cell Culture PBLs and TILs were thawed and cultured in RPMI-1640 containing 10% human AB sera for 4 hours at 37 C in 5% CO2 in multiwell plates or flasks depending on the cell number at 1 Â 106/mL. Cells stimulated by anti-CD3/anti-CD28-coated beads were first depleted of monocytes by a 2-hour adherence in tissue culture flasks.…”

Section: Collection Of Tumor Tissue and Peripheral Bloodmentioning

confidence: 99%

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Chang

Huang

et al. 2010

Cancer

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BACKGROUND: A study was carried out to determine the functional attributes of CD4 þ CD25 þ regulatory T cells in cancer progression by suppressing antitumor immunity. METHODS: Triple-color flow cytometry was used to study the phenotype expression of CD4 þ CD25 þ regulatory T cells and CD8 þ T cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) of 57 cases of stage I to IV endometrial carcinoma. The expression of T cell subsets was correlated with clinical prognostic parameters. RESULTS: The prevalence of CD4 þ CD25 þ T cells was significantly higher in the TILs than PBLs. The expression of CD4 þ CD25 þ regulatory T cells in cancer milieu correlated with the tumor grade, stage, and myometrium invasion. The expression of FOXP3 and GITR in CD4 þ CD25 þ regulatory T cells was lower in PBLs than TILs. Most tumor-infiltrating CD8 þ T cells were CD28 À CD45RA À CD45RO þ CCR7 À , suggesting good terminal differentiation. Most of them had an activated role with CD69 þ CD103 þ CD152 þ . Functionally, both granzyme B and perforin were scarcely expressed in peripheral regulatory T cells but were highly expressed in peripheral regulatory T cells in the tumor microenvironment. In contrast, CD8 þ cytotoxic T cells derived from PBLs expressed both granzyme B and perforin, and at significantly higher levels than in TILs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules can be synchronously up-regulated in CD8 þ cytotoxic T cells. CONCLUSIONS: Regulatory T cells in the tumor microenvironment may abrogate CD8 þ T cell cytotoxicity in a granzyme B-and perforin-dependent conduit. Decreases in both Th1 cytokines and cytotoxic enzymes are relevant for regulatory T cell-mediated restraint of tumor clearance in vivo. Of clinical significance, the expression of regulatory T cells in TILs may mediate T cell immune repression within cancer milieu and thus greatly correlate with cancer progression. Cancer 2010;116:5777-88.

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Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Cited by 181 publications

References 51 publications

Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

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Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Cited by 181 publications

References 51 publications

Immunoglobulin-like transcript receptors on human dermal CD14+dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Immunoglobulin-like transcript receptors on human dermal CD14+dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

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Product

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Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming