Impaired Tax‐specific T‐cell responses with insufficient control of HTLV‐1 in a subgroup of individuals at asymptomatic and smoldering stages

Abstract

Human T-cell leukemia virus type-1 (HTLV-1)-specific T-cell immunity, a potential antitumor surveillance system in vivo, is impaired in adult T-cell leukemia (ATL). In this study, we aimed to clarify whether the T-cell insufficiency in ATL is present before the disease onset or occurs as a consequence of the disease. We investigated T-cell responses against Tax protein in peripheral blood mononuclear cells (PBMCs) from individuals at earlier stages of HTLV-1-infection, including 21 asymptomatic HTLV-1 carriers (ACs) and four patients with smoldering-type ATL (sATL), whose peripheral lymphocyte count was in normal range. About 30% of samples tested showed clear Tax-specific interferon (IFN)-g producing responses. Proviral loads in this group were significantly lower than those in the other less-specific response group. The latter group was further divided to two subgroups with or without emergence of Tax-specific responses following depletion of CC chemokine receptor 4 (CCR4) + cells that contained HTLV-1-infected cells. In the PBMCs with Tax-specific responses, CD8 + cells efficiently suppressed HTLV-1 p19 production in culture. The remaining group without the emergence of Taxspecific response after CCR4 + cell-depletion included at least two sATL and one AC samples, which spontaneously produced HTLV-1 p19 in culture, where tetramer-binding, Tax-specific cytotoxic Tlymphocytes were either undetectable or unresponsive. Our results indicated that HTLV-1-specific T-cell responsiveness widely differed among HTLV-1 carriers, and that impairment of HTLV-1-specific T-cell responses was observed not only in advanced ATL patients but also in a subpopulation at earlier stages, which was associated with insufficient control of HTLV-1. (Cancer Sci 2009; 100: 481-489) H uman T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL).(1,2) Although the majority of HTLV-1-infected individuals remain asymptomatic throughout their lives, about 5% develop ATL during or after middle age and another small population develops HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and a variety of chronic inflammatory diseases.(3-7) Several epidemiological risk factors have been suggested to be associated with ATL development, including vertical transmission, gender (greater incidence in males than in females), (4,8) and increased numbers of abnormal lymphocytes associated with elevated HTLV-1 proviral loads.(9,10) However, elevation in HTLV-1 proviral loads is also a feature of HAM/TSP patients. (7,11) ATL is known to be an immunosuppressive condition. (21) General immunosuppression may be present not only in ATL patients, but also in asymptomatic HTLV-1 carriers (ACs) to some extent. (22,23) There is a clear difference between ATL and HAM/ TSP patients in the host T-cell responses against HTLV-1. Outgrowth of CD8 + HTLV-1-specific cytotoxic T-lymphocytes (CTLs) in response to in vitro stimulation is frequently found in peripheral blood mononuclear cell (PBMC) cultures from HAM/TSP pat...

Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study

“…The impairment of HTLV-1-specific T-cell responses was observed not only in patients with advanced ATL but also in a subpopulation of asymptomatic carriers, which was associated with insufficient control of HTLV-I. 42 Although whether donor anti-HTLV-I immunity can harness graft-versus-ATL responses is still elusive, further investigations are clearly needed to resolve this issue.…”

Clinical significance of CADM1/TSLC1/IgSF4 expression in adult T-cell leukemia/lymphoma

“…HTLV-1 proviral loads in some of the PBMC samples were measured by the Group of Joint Study on Predisponsing Factors of ATL Development (JSPFAD, Japan) as described previously. 21 The amount of HTLV-1 proviral DNA was calculated as the copy number of HTLV-1 per 100 PBMC ¼ ((copy number of pX)/(copy number of RNase P/2)) Â 100.…”

Host Immune System Abnormalities Among Patients with Human T-Lymphotropic Virus Type 1 (HTLV-1) - Associated Disorders

“…HTLV-1-specific CTLs are also present in ATL patients but do not expand sufficiently (Arnulf et al, 2004). Impairment of the HTLV-1 specific CTL response was observed in some individuals during the earlier stages of HTLV-1 infection (AC and smoldering ATL), as well as in advanced ATL patients (Shimizu et al, 2009). This observation suggests that the T-cell insufficiency in ATL patients is present prior to disease onset.…”