Diminished TCR signaling in cutaneous T cell lymphoma is associated with decreased activities of Zap70, Syk and membrane-associated Csk

Abstract

18). In addition, TCR engagecharacteristic of 'memory' T lymphocytes. 1-5 A high percentment results in Zap70 activation after its binding to the tyrosylage of the malignant cells constitutively express BE2, a late phosphorylated immunoreceptor tyrosine-based activation activation marker of 78 kDa, that appears on cloned normal motifs (ITAMs) of the chains and the CD3 complex 23,24 (for T cells only after stimulation with specific antigen, and on review see Ref. 25) and in rapid tyrosine phosphorylation and freshly isolated normal T cells in response to mitogens, 6,7 sugactivation of Syk. 26 The signaling initiated by TCR activation gesting that CTCL cells have been activated by their surroundis transmitted from the cell membrane through the cytoplasm ing dermal environment. Since CTCL lymphocytes can proto the nucleus and induces quiescent T cells to undergo cell liferate in the cutaneous compartment but are extremely division and maturation, processes critical for clonal expandifficult to cultivate in vitro, their neoplastic growth appears sion and initiation of the immune responses. to reflect in vivo stimulation, possibly through their TCR, orWe selected for investigation several immediate key reacantigen-independent pathways or cytokines. IL-7 might be one tions essential for T cell receptor-mediated signal transducof the required growth factors for CTCL cells in the skin since tion, proliferation and effector functions. Our results, based transgenic mice constitutively producing IL-7 developed on analysis of a limited sample of CTCL cells (from four extensive dermal infiltration followed by dermotropic lympatients), show nevertheless, common characteristics, ie phoma. 8,9 However, although IL-7 is produced by keradeficiencies in critical immediate functions associated with tinocytes, it is a weak in vitro CTCL mitogen, 10 and purified TCR activation. These include molecules participating in populations of CTCL cells were sustained in culture for only events proximal and distal to the TCR such as: (1) reduced a short period (such as a week) by mixtures of cytokines that levels of basal and stimulated tyrosyl-phosphorylated proteins include IL-7 and IL-2. 11,12 belonging to a wide range of signaling molecules; The preferential expression of CD45RO and the clonal TCR (2) suppressed specific activity of membrane-bound Csk and rearrangement suggest that CTCL clones have encountered a Lck; (3) failure to activate membrane-bound PTPase; (4) failure to activate Zap70 and to induce its association with the TCR chain; and (5) reduced expression and activity of Syk. LimitedCorrespondence: R Halaban, Department of Dermatology, Yale Unicomparative analysis with the CD4 + /CD45RO + subpopulation

Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling

“…20,29 It has already been noted that TCR signaling in CTCL tumor cells is reduced, along with decreased activity of Zap70, Syk, and membrane Csk. 41 Our results suggest that this deficiency may result at least in part from the overexpression of functional ILT2 inhibitory receptors. Finally, we found that circulating malignant Sézary cells may be separated from the nonmalignant reactive CD4 ϩ autologous T lymphocytes by means of anti-ILT2 mAb GHI/75.…”

Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma

“…44,45 A previous study has shown that the enzymatic activity of membrane-bound Csk is suppressed in tumor cells from patients with CTCL. 46 Furthermore, we found that the expression of Csk was down-regulated (albeit to a different extend) in the malignant CTCL cell lines relative to other T-cell lines ( Figure 4E). Collectively, these findings suggest that Blk is constitutively active in malignant CTCL cells and, further, that the aberrant activity is caused by autophosphorylation promoted by high abnormal expression of Blk combined with down-regulation of negative regulators of SFK activity such as Csk.…”

“…The observations that the endogenous SFK inhibitor, Csk, is down-regulated in the malignant T-cell lines and that the activity of membrane-bound Csk is suppressed in tumor cells from patients with CTCL support this hypothesis. 46 It is possible, however, that other SFKs or non-SFK tyrosine kinases also play a role in the constitutive activation of Blk.…”

Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation

“…Similar to IL-10R and TGF-b receptor II, malignant T cells from advanced disease typically display decreased surface expression of CD3 and/or exhibit resistance to TCR stimulation and apoptosis. 51,64 By targeting the benign T cells, SEs may still influence the malignant T cells even as they become resistant to TCR stimulation. Moreover, the proposed indirect mechanism implies that the pathogenic role of SEs is not limited to cases of patients expressing a SE-responsive TCR Vb on the malignant clone.…”