Human T-lymphotropic virus type 1 (HTLV-1) and regulatory T cells in HTLV-1-associated neuroinflammatory disease

Abstract

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL) and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4(+) T helper (Th) cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naïve CD4(+) T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg) cells. The CD4(+)CD25(+)CCR4(+) T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4(+)CD25(+)CCR4(+) T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-γ, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-γ(+) T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease.

Keywords: ATL; CD4+CD25+CCR4+ T cell; HAM/TSP; HTLV-1; exFoxp3+ cell; immune-dysfunction; inflammation; regulatory T cell.

Figure 1.

T cell subsets of CD4⁺ T helper cells. Th cells are differentiated from naïve CD4⁺ T cells into 4 major lineages: Th1, Th2, Th17, and T-regulatory (Treg) cells. Each Th subset exhibits characteristic functions, patterns of cytokine secretion, and expression of specific chemokine receptors.

Figure 2.

Cellular components of CD4⁺CD25⁺CCR4⁺ T cells in healthy donors and HAM/TSP patients. In healthy donors, the CD4⁺CD25⁺CCR4⁺ T cell population primarily consists of suppressive T cell subsets, such as Treg and Th2, whereas that of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients consists of an increased number of IFN-γ-producing Foxp3⁻CD4⁺CD25⁺CCR4⁺ T cells (T_HAM cells).

Figure 3.

Differential immune responses and T_HAM/Treg ratios in CD4⁺CD25⁺CCR4⁺ T cells in HAM/TSP and adult T cell leukemia/lymphoma (ATL) patients.

Figure 4.

Scheme of proportion of each cellular component in CD4⁺CD25⁺CCR4⁺ T cells of healthy donors, asymptomatic carriers (AC), and patients with HAM/TSP or ATL. Although the proportion of Foxp3⁺ cells among the CD4⁺CD25⁺CCR4⁺ T cells is lower in HAM/TSP patients, the overall number of CD4⁺Foxp3⁺ cells in HAM/TSP patients is higher than that in healthy donors. In ATL patients, the majority of CD4⁺CD25⁺CCR4⁺ T cells are Foxp3⁺ cells.

Figure 5.

Differential fate of HTLV-1-infected CD4⁺CD25⁺CCR4⁺ T cells in HAM/TSP and ATL patients. After HTLV-1 infection, CD4⁺CD25⁺CCR4⁺ T cells in HAM/TSP patients, which are primarily Th2 and Treg cells before infection, become IFN-γ⁺Foxp3⁻ T cells (T_HAM cells) with high levels of intracellular HTLV-1 tax expression. In ATL patients, leukemogenesis develops and the Foxp3⁺ Treg phenotype is maintained.

Figure 6.

Increased HTLV-1 tax mRNA expression in CD4⁺CD25⁺CCR4⁺ T cells in HAM/TSP patients. The HTLV-1 proviral load in CD4⁺CD25⁺CCR4⁺ T cells from HAM/TSP and ATL patients was quantified by real-time PCR (left panel, n = 3). Expression levels of HTLV-1 tax mRNA (center panel, HAM/TSP: n = 4, ATL: n = 3) and HBZ mRNA (right panel, n = 5) in CD4⁺CD25⁺CCR4⁺ T cells from HAM/TSP and ATL patients were quantified by real-time RT-PCR. Data are presented as mean ± standard error.