High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma.

In early-stage cutaneous T-cell lymphoma (CTCL), malignant T cells are confined to skin and are difficult to isolate and discriminate from benign reactive cells. We found that T cells from CTCL skin lesions contained a population of large, high-scatter, activated skin homing T cells not observed in other inflammatory skin diseases. High-scatter T (T(HS)) cells were CD4(+) in CD4(+) mycosis fungoides (MF), CD8(+) in CD8(+) MF, and contained only clonal T cells in patients with identifiable malignant Vβ clones. T(HS) cells were present in the blood of patients with leukemic CTCL, absent in patients without blood involvement, and contained only clonal malignant T cells. The presence of clonal T(HS) cells correlated with skin disease in patients followed longitudinally. Clonal T(HS) cells underwent apoptosis in patients clearing on extracorporeal photopheresis but persisted in nonresponsive patients. Benign clonal T-cell proliferations mapped to the normal low-scatter T-cell population. Thus, the malignant T cells in both MF and leukemic CTCL can be conclusively identified by a unique scatter profile. This observation will allow selective study of malignant T cells, can be used to discriminate patients with MF from patients with other inflammatory skin diseases, to detect peripheral blood involvement, and to monitor responses to therapy.

[1]  James J. Campbell,et al.  Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. , 2010, Blood.

[2]  R. Clark.  Skin-resident T cells: the ups and downs of on site immunity. , 2010, The Journal of investigative dermatology.

[3]  Thomas Gebhardt,et al.  Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus , 2009, Nature Immunology.

[4]  Katherine G. Evans,et al.  Update on treatment of cutaneous T-cell lymphoma , 2009, Current opinion in oncology.

[5]  R. Clark,et al.  Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells , 2008, The Journal of experimental medicine.

[6]  James T. Elder,et al.  Induction of IL-17+ T Cell Trafficking and Development by IFN-γ: Mechanism and Pathological Relevance in Psoriasis1 , 2008, The Journal of Immunology.

[7]  T. Golub,et al.  Lesional gene expression profiling in cutaneous T-cell lymphoma reveals natural clusters associated with disease outcome. , 2007, Blood.

[8]  Khusru Asadullah,et al.  Immunopathogenesis of psoriasis , 2007, Experimental dermatology.

[9]  Nicola Pimpinelli,et al.  Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). , 2007, Blood.

[10]  O. Boyman,et al.  α1β1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis , 2007, Nature Medicine.

[11]  C. Capristo,et al.  Immune dysregulation in atopic dermatitis. , 2006, Allergy and asthma proceedings.

[12]  R. Clark,et al.  Response to Comment on “The Vast Majority of CLA+ T Cells Are Resident in Normal Skin” , 2006, The Journal of Immunology.

[13]  S. Sicherer,et al.  Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects. , 2006, The Journal of allergy and clinical immunology.

[14]  C. Klemke,et al.  Paucity of FOXP3+ cells in skin and peripheral blood distinguishes Sézary syndrome from other cutaneous T-cell lymphomas , 2006, Leukemia.

[15]  R. Clark,et al.  A novel method for the isolation of skin resident T cells from normal and diseased human skin. , 2006, The Journal of investigative dermatology.

[16]  R. Clark,et al.  The Vast Majority of CLA+ T Cells Are Resident in Normal Skin1 , 2006, The Journal of Immunology.

[17]  Nicola Pimpinelli,et al.  WHO-EORTC classification for cutaneous lymphomas. , 2005, Blood.

[18]  Jennifer Trinh,et al.  Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. , 2005, Blood.

[19]  S. Sicherer,et al.  Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2009. , 2004, The Journal of allergy and clinical immunology.

[20]  Antonio Lanzavecchia,et al.  Central memory and effector memory T cell subsets: function, generation, and maintenance. , 2004, Annual review of immunology.

[21]  E. Vonderheid,et al.  The Sézary syndrome: hematologic criteria. , 2003, Hematology/oncology clinics of North America.

[22]  R. Gascoyne,et al.  Aberrant expression of T-plastin in Sezary cells. , 2003, Cancer research.

[23]  T. Kupper,et al.  Monitoring the decrease of circulating malignant T cells in cutaneous T-cell lymphoma during photopheresis and interferon therapy. , 2003, Archives of dermatology.

[24]  A. Varghese,et al.  Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. , 2003, Archives of dermatology.

[25]  M. Duvic,et al.  A stable aberrant immunophenotype characterizes nearly all cases of cutaneous T-cell lymphoma in blood and can be used to monitor response to therapy , 2002, BMC clinical pathology.

[26]  G. Pinkus,et al.  Increased CCR4 expression in cutaneous T cell lymphoma. , 2002, The Journal of investigative dermatology.

[27]  V. Rutten,et al.  Immune dysregulation in atopic dermatitis. , 2002, Veterinary immunology and immunopathology.

[28]  R. Dummer,et al.  The use of anti‐T‐cell receptor‐Vβ antibodies for the estimation of treatment success and phenotypic characterization of clonal T‐cell populations in cutaneous T‐cell lymphomas , 2002, British journal of haematology.

[29]  H. Pilch,et al.  Improved Assessment of T-Cell Receptor (TCR) VB Repertoire in Clinical Specimens: Combination of TCR-CDR3 Spectratyping with Flow Cytometry-Based TCR VB Frequency Analysis , 2002, Clinical and Vaccine Immunology.

[30]  M. Polansky,et al.  Variable CD7 expression on T cells in the leukemic phase of cutaneous T cell lymphoma (Sézary syndrome). , 2001, The Journal of investigative dermatology.

[31]  J. V. van Dongen,et al.  Molecular and flow cytometric analysis of the Vbeta repertoire for clonality assessment in mature TCRalphabeta T-cell proliferations. , 2001, Blood.

[32]  N. Dang,et al.  Absence of CD26 expression is a useful marker for diagnosis of T-cell lymphoma in peripheral blood. , 2001, American journal of clinical pathology.

[33]  S. Ugurel,et al.  CD4(+)CD7(-) T cells compose the dominant T-cell clone in the peripheral blood of patients with Sézary syndrome. , 2001, Journal of the American Academy of Dermatology.

[34]  S. Sakaguchi.  Regulatory T cells , 2000, Cell.

[35]  T. Petrella,et al.  Value of clonality studies of cutaneous T lymphocytes in the diagnosis and follow‐up of patients with mycosis fungoides , 1998, The Journal of pathology.

[36]  E. Vonderheid,et al.  Failure of anti-T-cell receptor V beta antibodies to consistently identify a malignant T-cell clone in Sézary syndrome. , 1996, The American journal of pathology.

[37]  B. Kotzin,et al.  Analysis of clonal CD8+ T cell expansions in normal individuals and patients with rheumatoid arthritis. , 1995, Journal of immunology.

[38]  D. Fivenson,et al.  Localization of clonal T cells to the epidermis in cutaneous T-cell lymphoma. , 1994, Journal of the American Academy of Dermatology.

[39]  J. Sklar,et al.  Detection of clonal T-cell receptor gamma gene rearrangements in early mycosis fungoides/Sezary syndrome by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR/DGGE). , 1994, The Journal of investigative dermatology.

[40]  C. Janeway.  The co-receptor function of CD4. , 1991, Seminars in immunology.

[41]  J. Hoxie,et al.  Alterations in T4 (CD4) protein and mRNA synthesis in cells infected with HIV. , 1986, Science.

[42]  J. Boer,et al.  Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome. , 2009, Blood.

[43]  R. Clark,et al.  IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. , 2007, Blood.

[44]  O. Boyman,et al.  Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. , 2007, Nature medicine.