Where have all the T cells gone?

The majority of cutaneous T-cell lymphomas (CTCLs) consist of clonal proliferations of skin-trafficking T cells that are usually CD4⁺/CD45RO⁺/CCR4⁺/CLA⁺/CD26^-. The malignant T cells frequently exhibit a Th2 cytokine profile with up-regulation of glutamate acetyltransferase 3 (GATA-3), enhanced interleukin-4 production, and depressed interferon-gamma production. Furthermore, signal transducers and activators of transcription 4 (Stat 4) expression by the malignant T cells appears to be markedly diminished. Progressive disease is typically associated with defects in many aspects of the cellular immune response including T-cell responses to antigens, cell-mediated cytotoxicity, and abnormalities of dendritic cell function. These abnormalities have been attributable to expansion of the malignant T cells with increased production of Th2 cytokines that ultimately impedes the normal functions of cellular immunity.

In this issue of Blood, Yawalkar and colleagues (page 4059), using flow cytometry and complementarity-determining region 3 spectratype analysis of peripheral blood T-cell receptor beta-variable (Vbeta) family expression, elegantly demonstrate that among 22 patients with CTCL, those with advanced disease virtually always exhibit marked losses of expression of the normal T-cell repertoire. These observations were not made among patients with psoriasis or among healthy volunteers. Therefore, loss of the normal T-cell repertoire may at least partially account for deficiencies in cellular immunity as the ability to respond to a full range of antigens and the capacity for normal cytokine production may be compromised. Surprisingly, 50% of patients with early stages of CTCL also exhibited similar losses of Vbeta T-cell families. Previous studies of early-stage patients have failed to demonstrate significant abnormalities of cellular immunity. However, rigorous analysis of immune function in such patients has not been undertaken. Thus, the full relationship of these findings to the immune deficiency remains to be determined.

The mechanisms underlying the loss of T-cell families has not been defined. Yawalkar and colleagues point to a similar loss of the T-cell repertoire during HIV infection and, thus, implicate an unidentified retrovirus or other infectious agent as the cause of the phenomenon. Apparently, at least a partial restoration of T-cell families occurs if patients improve clinically during treatment (T. S. Kupper, oral communication, July 2003). This is reminiscent of our observations related to the significant restoration of cellular immune functions. We observed that a complete remission can be induced with biologic response modifiers with complete disappearance of the malignant T cells. Normalization of cell-mediated cytotoxicity, dendritic cell numbers, and function and enhanced production of interferon gamma and interleukin-12 occur during remission of patients with Sezary syndrome. These findings suggest an alternative possibility in that a soluble factor produced by the malignant T cells may be playing an important role to inhibit the proliferation of normal T cells as well as dendritic cells and to depress Th1 cytokine production. Substantial evidence exists to support this contention. Nevertheless, the outstanding work of Yawalkar and colleagues points to another cause of the immune deficiency in CTCLs and yields additional clues to the potential etiology and pathogenesis of CTCLs.