Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins

Abstract

Bacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell IntroductionThe etiology of cutaneous T-cell lymphoma (CTCL), the most common type of T-cell lymphoma, remains poorly understood, but occupational exposures, infectious agents, and genetic mutations have been proposed as etiologic factors (see reviews [1][2][3][4][5] ). Mycosis fungoides (MF) and the leukemic variant Sezary syndrome (SS) are the 2 major clinical variants of CTCL. In the initial phase, which can last a number of years, MF presents as flat erythromatous skin patches, resembling chronic inflammation seen in chronic skin infections, psoriasis, and eczema. In the later stages, MF lesions gradually form plaques and overt tumors and eventually involve lymph nodes and internal organs. The early skin lesions in CTCL contain a heterogeneous cell population, including malignant cells that phenotypically resemble normal activated CD4 ϩ T lymphocytes and a mixture of nonmalignant tumor-infiltrating T cells, dendritic cells, macrophages, and other inflammatory cells. 1-5 SS, a leukemic and erythrodermic variant of CTCL, is characterized by the presence of circulating lymphocytes with atypical cerebriform nuclei (Sezary cells) in the skin, lymph nodes, and peripheral blood. 1 It is a more aggressive form of CTCL, with a mean survival of 3 years from the time of diagnosis.The role of chronic inflammation as a critical component in tumor progression has recently attracted much attention. It has become clear that the tumor microenvironment, which is largely made up of inflammatory cells, is a component of the malignant tumors (reviewed in de Visser et al 6 ). For instance, viral-antigenspecific, tumor-infiltrating CD4 ϩ T cells enhanced the neoplastic progression into invasive cancer in a model of squamous epithelial cell carcinogenesis induced by human papilloma virus oncogenes. 7 Furthermore, gene-expression profiling in follicular lymphomas indicated that the patient survival correlated with the molecular features of nonmalignant immune cells present in the tumor at diagnosis. 8 Several lines of evidence suggest that in CTCL there is a cross talk between malignant and nonmalignant T lymphocytes, keratinocytes, and dendritic cells. [9][10] During the course of the disease, a shift in the composition of infiltrating T cells appears to take place and the interactions between malignant and nonmalignant cells change. In the early stages of the disease, the infiltrate consists primarily of nonmalignant T-helper 1 (TH1) cells and cytotoxic CD8 ϩ T cells that appear to control the malignant cells via inhibitory cytokines such as interferon gamma and, possibly, direct cytotoxicity. [11][12][13] At the later stages of the disease, TH2 cells and cytokines seem to predominate. 11,12 Because malignant cells derived from MF tumors produce large amounts of IL-5, IL-6, and IL-13, it is likely ...

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

“…After 3 days of culture, 7 mCi of [ 3 H]thymidine was added to each well and incorporation determined as described. 35 …”

COX-2-dependent PGE2 acts as a growth factor in mycosis fungoides (MF)

“…MyLa1929 was established from an early lesion, whereas the MyLa2000 and MyLa2059 cell lines were from advanced lesions. 13 HH 15 and Hut78 16 are malignant CTCL cell lines and were cultured under the same conditions. MySi is a non-malignant CD8 þ T-cell line from the skin, 13 and was cultured in RPMI-1640, 10% human serum (Blood Bank, State University Hospital, Copenhagen, Denmark), 2 mM L-glutamine, 0.1 mg/ml penicillin/streptomycin and 10 3 U/ml IL-2 (Proleukin, Chiron, Emeryville, CA, USA).…”

“…MyLa1929, MyLa2000 and MyLa2059 are malignant T-cell lines established from the skin of patients with CTCL, 13,14 and were cultured in RPMI-1640 (Sigma-Aldrich) with 10% fetal bovine serum (Life Technologies, Roskilde, Denmark), 2 mM L-glutamine and 0.1 mg/ml penicillin/streptomycin (all from Sigma-Aldrich). MyLa1929 was established from an early lesion, whereas the MyLa2000 and MyLa2059 cell lines were from advanced lesions.…”

“…MySi is a non-malignant CD8 þ T-cell line from the skin, 13 and was cultured in RPMI-1640, 10% human serum (Blood Bank, State University Hospital, Copenhagen, Denmark), 2 mM L-glutamine, 0.1 mg/ml penicillin/streptomycin and 10 3 U/ml IL-2 (Proleukin, Chiron, Emeryville, CA, USA). MyLa1850 is a non-malignant CD4 þ T-cell line from the same patient as MyLa2000, 13,14 and was cultured as MySi with 25 ng/ml IL-4 (Leinco Technologies, St Louis, MO, USA).…”

FOXP3+ regulatory T cells in cutaneous T-cell lymphomas: association with disease stage and survival

“…[12][13][14][15] The Jurkat cell line was transfected with haemagglutinin (HA)-tagged FOXP3 or a vector control as described. 16 …”