Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma

Yawalkar, Nikhil; Ferenczi, Katalin; Jones, David A.; Yamanaka, Keiichi; Suh, Ki-Young; Sadat, Sarah; Kupper, Thomas S.

doi:10.1182/blood-2003-04-1044

Cited by 155 publications

(134 citation statements)

References 40 publications

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“…4). In contrast to the previously described limited expression of V␤ by T cells from mycosis fungoides and psoriasis skin lesions, we found no discernable V␤ bias among T cells infiltrating normal skin (11)(12)(13)(14)(15)(16)). …”

Section: Skin Resident T Cells Have a Highly Diverse Tcr Repertoirecontrasting

confidence: 55%

The Vast Majority of CLA+ T Cells Are Resident in Normal Skin

Clark

Chong

Mirchandani

et al. 2006

The Journal of Immunology

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There are T cells within normal, noninflamed skin that most likely conduct immunosurveillance and are implicated in the development of psoriasis. We isolated T cells from normal human skin using both established and novel methods. Skin resident T cells expressed high levels of CLA, CCR4, and CCR6, and a subset expressed CCR8 and CXCR6. Skin T cells had a remarkably diverse TCR repertoire and were mostly Th1 memory effector cells with smaller subsets of central memory, Th2, and functional T regulatory cells. We isolated a surprising number of nonexpanded T cells from normal skin. To validate this finding, we counted T cells in sections of normal skin and determined that there are ∼1 × 106 T cells/cm2 normal skin and an estimated 2 × 1010 T cells in the entire skin surface, nearly twice the number of T cells in the circulation. Moreover, we estimate that 98% of CLA+ effector memory T cells are resident in normal skin under resting conditions. These findings demonstrate that there is a large pool of memory T cells in normal skin that can initiate and perpetuate immune reactions in the absence of T cell recruitment from the blood.

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Section: Skin Resident T Cells Have a Highly Diverse Tcr Repertoirecontrasting

confidence: 55%

The Vast Majority of CLA+ T Cells Are Resident in Normal Skin

Clark

Chong

Mirchandani

et al. 2006

The Journal of Immunology

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697

664

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“…We have shown in our study that Vb flow cytometry is quantitative, and the quantitative nature of Vb expression can be further improved by incorporating the other immunophenotyping data such as CD4:CD8 ratio, absolute CD3 þ CD4 þ CD26À cells, or CD3 þ CD4 þ cells into the flow cytometric analysis, validating the proposal by earlier pilot studies. 25,37 We have also shown that Sézary cell counting by morphologic analysis is extremely insensitive and would miss a high proportion of cases with a high tumor burden compared with flow cytometric analysis (Figure 4). Using flow cytometric Vb expression analysis, at least 12 patients were upstaged from B1 to B2, a change in peripheral blood stage with prognostic implications.…”

Section: Discussionmentioning

confidence: 98%

Flow cytometric detection of peripheral blood involvement by mycosis fungoides and Sézary syndrome using T-cell receptor Vβ chain antibodies and its application in blood staging

et al. 2010

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Peripheral blood involvement has been recognized as an adverse prognostic factor in patients with mycosis fungoides and Sé zary syndrome. However, accurate identification and enumeration of the neoplastic cells in these diseases can be challenging. We assessed the clinical utility of flow cytometric immunophenotypic analysis of T-cell receptor Vb expression in 82 mycosis fungoides and 6 Sé zary syndrome patients, with an atypical T-cell immunophenotype, or abnormal CD4:CD8 ratio, identified from peripheral blood specimens of 723 patients submitted for routine mycosis fungoides/Sé zary syndrome blood staging. To improve detection sensitivity, Vb expression was analyzed on gated CD3 þ CD4 þ T cells or T cells with an aberrant immunophenotype, if present. The flow cytometric results were compared with traditional morphologic assessment (n ¼ 88) and molecular methods to assess the T-cell receptor c or b genes (n ¼ 41 tested in parallel). Flow cytometric immunophenotyping yielded a clonal Vb pattern in 60/82 mycosis fungoides and 6/6 Sé zary syndrome patients. By contrast, flow cytometric Vb was negative in all 10 healthy donors and 18 control patients, showing a specificity of 100% and concordance with molecular testing of 86%. Using flow cytometric Vb results instead of morphologic assessment, 12 patients were upstaged from B1 to B2, and 20 patients from B0 to B1 (Po0.0001). The 12 upstaged B2 patients had no morphologic evidence of involvement, but had an aggressive clinical course similar to those staged by traditional morphologic assessment (median survival 27 vs 41 months, log-rank P ¼ 0.701). In 30/44 patients with a tumor-associated Vb expression, a single Vb tube was used to monitor treatment response. In conclusion, flow cytometric Vb analysis is rapid and convenient, can assess T-cell clonality and tumor quantity simultaneously, and is useful both in initial blood staging and monitoring tumor burden during therapy in patients with mycosis fungoides or Sé zary syndrome.

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“…In addition, CTCL is associated with a significant loss of the T-cell repertoire, analogous to that observed in HIV infection. T-cell receptor (TCR) diversity within multiple TCR beta-variable (Vb) families was analyzed using complementarity-determining region 3 (CDR3) spectratyping and combined with a quantitative analysis of TCR-Vb usage by flow cytometry [58]. In patients with advanced-stage disease, and half of patients with limited-stage disease, a dramatic loss of TCR diversity was observed.…”

Section: Immunopathogenesismentioning

confidence: 99%

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

Wilcox

2011

American J Hematol

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Disease overview: Cutaneous T‐cell lymphomas are a heterogenous group of T‐cell lymphoproliferative disorders involving the skin, the majority of which may be classified as Mycosis fungoides (MF) or Sézary syndrome (SS).Diagnosis: The diagnosis of MF or SS requires the integration of clinical and histopathologic data.Risk‐adapted therapy: Tumor, node, metastasis, and blood (TNMB) staging remains the most important prognostic factor in MF/SS and forms the basis for a “risk‐adapted,” multidisciplinary approach to treatment. For patients with disease limited to the skin, expectant management or skin‐directed therapies is preferred, as both disease‐specific and overall survival for these patients is favorable. In contrast, patients with advanced‐stage disease with significant nodal, visceral, or blood involvement are generally approached with biologic‐response modifiers, denileukin diftitox, and histone deacetylase inhibitors before escalating therapy to include systemic, single‐agent chemotherapy. Multiagent chemotherapy may be used for those patients with extensive visceral involvement requiring rapid disease control. In highly‐selected patients with disease refractory to standard treatments, allogeneic stem‐cell transplantation may be considered. Am. J. Hematol., 2011. © 2011 Wiley‐Liss, Inc.

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Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma

Cited by 155 publications

References 40 publications

The Vast Majority of CLA+ T Cells Are Resident in Normal Skin

The Vast Majority of CLA+ T Cells Are Resident in Normal Skin

Flow cytometric detection of peripheral blood involvement by mycosis fungoides and Sézary syndrome using T-cell receptor Vβ chain antibodies and its application in blood staging

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

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