IFN‐γ production in response to Tax 161–233, and frequency of CD4⁺ Foxp3⁺ and Lin⁻ HLA‐DR^high CD123⁺ cells, discriminate HAM/TSP patients from asymptomatic HTLV‐1‐carriers in a Peruvian population

Abstract

Summary Human T‐lymphotropic virus 1 (HTLV‐1) can cause HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP). The objective of this study was to gain insight into the pathogenesis of HAM/TSP by focusing on the CD8+ T‐cell response. Twenty‐three HTLV‐1‐seronegative controls (SC), 29 asymptomatic HTLV‐1 carriers (AC) and 48 patients with HAM/TSP were enrolled in the study. We evaluated the production of interferon‐γ (IFN‐γ) in peripheral blood mononuclear cells stimulated with Tax overlapping peptides, the expression of genes related to the CD8+ cytotoxic T‐cell response, the frequency of CD4+ Foxp3+ cells and of dendritic cells, and the HTLV‐1 provirus load (PVL). The frequency of cells producing IFN‐γ in response to Tax 161–233, but not to Tax 11–19, discriminated patients with HAM/TSP from AC. The increased pro‐inflammatory response observed in patients with HAM/TSP was shared by AC with a high PVL, who also exhibited lower levels of granzyme H mRNA in unstimulated CD8+ T cells than AC with a low PVL. Patients with HAM/TSP showed higher frequencies of CD4+ Foxp3+ cells and lower frequencies of plasmacytoid dendritic cells (pDC) than AC. Our findings are consistent with a model in which HTLV‐1, along with the host genetic background, drives quantitative and qualitative changes in pDC and CD4+ Foxp3+ cells that lead to a predominance of inflammatory responses over lytic responses in the CD8+ T‐cell response of individuals predisposed to develop HAM/TSP.

High IFN-γ/IL-10 Expression Ratio and Increased Frequency of Persistent Human T-Cell Lymphotropic Virus Type 1-Infected Clones Are Associated with Human T-Cell Lymphotropic Virus Type 1-Associated Myelopathy/Tropical Spastic Paraparesis Development

“…In addition, ACs with high PVL presented inflammatory profiles similar to HAM/TSP patients, in accordance to previous studies [36,37], but only to HAM/TSP patients with low PVL, indicating that factors other than PVL are involved in disease outcome. Since not all HAM/TSP patients present high PVL, the additional evaluation of the inflammatory profile considering the ratio between IFN-γ and IL-10 mRNA expression could aid the identification of ACs at a higher risk for development of HAM/TSP irrespective of the PVL level.…”

HTLV-1-associated infective dermatitis demonstrates low frequency of FOXP3-positive T-regulatory lymphocytes

“…A strong negative correlation between the frequency of CD4+ FoxP3+ Tax-Tregs and the rate of cytotoxic T-cell-mediated lysis of HTLV-1-infected cells has been demonstrated [21]. Whereas ATLL cells are known to exhibit strong immunosuppressive activity [23] and a CD4+ CD25+ phenotype with at least some expression of FoxP3 (as opposite as any other lymphomas) [24] and patients with HAM/TSP have been found to show high frequencies of CD4+ FoxP3+ cells in peripheral blood, [25] the status of FoxP3+ cells in skin specimens of ID, to our knowledge, has not been studied.…”

Preapoptotic protease calpain-2 is frequently suppressed in adult T-cell leukemia

“…Indeed, aberrant proliferation of Treg cells is considered the main cause of immunodeficiency in ATL patients because of their innate immunosuppressive functions, 19 whereas abnormal production of interferon g from infected Treg cells might induce chronic spinal inflammation in HAM/TSP patients. 20 Given the list of our 17 classifier proteins, activation of signal transducer and activator of transcription 1-a/b is the well-known key factor for HAM/TSP, 21 whereas upregulation of heat shock 70-kDa protein 1A/1B, CH10, and PTMS were reported in many other types of tumors. [22][23][24] The association of these 4 proteins with the etiology of HAM/TSP and ATL would be evident according to the previous work, supporting that our other candidates might similarly have a direct impact on the transformation of Treg cells after infection of HTLV-1.…”