Reduced Frequency, Diversity, and Function of Human T Cell Leukemia Virus Type 1-Specific CD8+ T Cell in Adult T Cell Leukemia Patients

Abstract

Human T cell lymphotropic virus type 1 (HTLV-1)-specific CTL are thought to be immune effectors that reduce the risk of adult T cell leukemia (ATL). However, in vivo conditions of anti-HTLV-1 CTL before and after ATL development have yet to be determined. To characterize anti-HTLV-1 CTL in asymptomatic HTLV-1 carriers (AC) and ATL patients, we analyzed the frequency and diversity of HTLV-1-specific CD8+ T cells in PBMC of 35 AC and 32 ATL patients using 16 distinct epitopes of HTLV-1 Tax or Env/HLA tetramers along with intracellular cytolytic effector molecules (IFN-γ, perforin, and granzyme B). Overall frequency of subjects possessing Tax-specific CD8+ T cells was significantly lower in ATL than AC (53 vs 90%; p = 0.001), whereas the difference in Env-specific CD8+ T cells was not statistically significant. AC possessed Tax11–19/HLA-A*0201-specific tetramer+ cells by 90% and Tax301–309/HLA-A*2402-specific tetramer+ cells by 92%. Some AC recognized more than one epitope. In contrast, ATL recognized only Tax11–19 with HLA-A*0201 and Tax301–309 with HLA-A*2402 at frequencies of 30 and 55%. There were also significant differences in percentage of cells binding Tax11–19/HLA-A*0201 and Tax301–309/HLA-A*2402 tetramers between AC and ATL. Anti-HTLV-1 Tax CD8+ T cells in AC and ATL produced IFN-γ in response to Tax. In contrast, perforin and granzyme B expression in anti-HTLV-1 CD8+ T cells of ATL was significant lower than that of AC. Frequency of Tax-specific CD8+ T cells in AC was related to proviral load in HLA-A*0201. These results suggest that decreased frequency, diversity, and function of anti-HTLV-1 Tax CD8+ T cell clones may be one of the risks of ATL development.

Risk of human T‐lymphotropic virus type I‐associated diseases in Jamaica with common HLA types

“…1 Our finding that common B alleles were associated with a 2-fold higher risk of ATL and a 0.4 log 10 higher HTLV-I proviral load suggests that the presence of immunocytes capable of recognizing diverse epitopes may reduce the risk of evolution to frank leukemia/lymphoma, perhaps through control of HTLV-I-infected cells. 17 Ultimately, a large study that takes other genetic and environmental influences into account will be needed to disentangle the roles of HLA and other host factors in controlling HTLV-I infection and in determining the risk of ATL and HAM/TSP.…”

High Frequencies of Functionally Competent Circulating Tax-Specific CD8+ T Cells in Human T Lymphotropic Virus Type 2 Infection

“…B, Representative plots showing the differential levels of expression of perforin and granzyme B in Tax2 (11)(12)(13)(14)(15)(16)(17)(18)(19) pentamer binding CD8 Taking into consideration that HTLV-2 is less pathogenic than HTLV-1, this highly focused response restricted to HLA-A*0201 could well represent an effective immune control mechanism. Indeed, Kozako et al reported that a reduced frequency and diversity, associated with impaired function, of specific anti-Tax1 CTLs could represent a risk for ATLL development (29). In other viral infections, high levels of CTL responses against single epitopes can represent effective control of viral burden and a relative protection against disease development.…”

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

“…This observation suggests that the T-cell insufficiency in ATL patients is present prior to disease onset. In addition, a recent report indicated that, in comparison to ACs, ATL patients have a smaller and less diverse population of HTLV-1 specific CD8 + T cells, as well as lower anti-HTLV-1 CD8 + T cell expression of perforin and granzyme B (Kozako et al, 2006). Thus, the decreased number and functional impairment of CTLs might contribute to the onset and progression of ATL.…”