Restoration of peripheral blood T cell repertoire complexity during remission in advanced cutaneous T cell lymphoma

Abstract

In advanced stages, cutaneous T cell lymphomas (CTCL) are associated with increased mortality from infections and also increased susceptibility to skin malignancies. In this study, we analyzed the complexity of the peripheral blood T cell repertoire with a sensitive b-variable (BV) complementarity-determining region 3 (CDR3) spectratyping analysis and flow cytometry in three-stage IV CTCL/Sezary syndrome patients who achieved complete clinical remission after therapy. The T cell repertoire of peripheral blood T cells before treatment was profoundly abnormal across multiple BV subfamilies. Following treatment, CDR3 spectratype patterns showed dramatic restoration of normal diversity and complexity. However, absolute CD4 counts across multiple BV families remained low for many months, even after identifiable circulating malignant T cell populations were eliminated. These data suggest that the diversity of the T cell repertoire can be recovered after successful treatment of even advanced CTCL.

Fig. 1

Absolute CD4 count, TREC levels, and plasma IL-7 levels. Absolute CD4 count was lower than normal range after successful treatments. TREC levels were lower than normal controls before treatment, and the levels did not increase enough after patients had achieved complete remissions. Plasma IL-7 levels were still higher than normal after achieving complete remission

Fig. 2

Restoration of T cell repertoire diversity following induction of remission in CTCL. TCR BV CDR3 spectratyping profiles (a–c) and combination of qualitative (CDR3 spectratyping) and quantitative (flow cytometry) analysis plots (d–f) give a better visual assessment of the global reduction of the TCR diversity in CTCL. The CDR3 spectratype of CD3+ T cells from a representative healthy donor (panel a) shows a highly diverse profile in all BV subfamilies, reflecting a heterogeneous TCR repertoire. The combination plot (panel d) displays BV subfamilies along the x-axis, CDR3 length distribution (in amino acids) along the y-axis, and absolute number of BV+CD3+ T cells/μL along the z-axis as measured by flow cytometry. Analysis of peripheral CD3+cells from a patient with stage IVA CTCL (Patient A) shows a markedly reduced spectratype complexity (panel b, see also Tables 1 and 2) and a numerically expanded malignant clone (BV 11, panel e). Analysis of the same patient after induction of CR shows improved, though still some abnormal, CDR3 spectratype (panel c) with the restriction of diverse T cells in the peripheral blood (panel f)