HTLV-1 Tax Specific CD8+ T Cells Express Low Levels of Tim-3 in HTLV-1 Infection: Implications for Progression to Neurological Complications

The T cell immunoglobulin mucin 3 (Tim-3) receptor is highly expressed on HIV-1-specific T cells, rendering them partially “exhausted” and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), we investigated the expression of the Tim-3 receptor on CD8+ T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8+ and CD4+ T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8+ T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3+ and Tim-3− fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications

Patients description.

<p>ND = not detected, N/A  = not available.</p

Tim-3, PD-1 and Tax co-expression on T cells.

<p>(A) Plots demonstrate representative co-staining for Tax, PD-1 and Tim-3 on CD8+ and CD4+ T cells by flow cytometry following 24 hours incubation for the induction of Tax in two representative HTLV-1 infected patients. An isotype control was used to delineate the measurements for Tax expression. (B, C) Plots and graph depict the co-expression of Tim-3 and PD-1 by the indicated cytokines after 12 hr in vitro culture of 1×10⁶ PBMC from 4 HTLV-1 infected patients. A representative donor is shown in B.</p

Tim-3 expression on HTLV-1-specific CD8+ T cells in HTLV-1 infection.

<p>PBMC from HLA-A*02+ chronically HTLV-1 infected individuals were stained with matched HLA pentamers presenting CMV and HTLV-1 epitopes, and with an anti-Tim-3 antibody. Shown are representative flow cytometry data from one HTLV-1-infected person using HLA-A*02 pentamers presenting the (A) HTLV-I-Tax 11–19 epitope and, (B) CMV-pp65 epitope ‘NLVPMVATV’. (C, D) Plots show co-expression of Tim-3 (upper panel) and PD-1 (lower panel) with the respective HLA-A*02 pentamers (Tax (left) and CMVpp65 (right)) from the gated CD8+ T population depicted in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001030#pntd-0001030-g002" target="_blank">Fig 2</a> A, B. The percentages of cells in the upper left and right quadrants of the flow plots demonstrated in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001030#pntd-0001030-g002" target="_blank">Figure 2C, D</a> reflect only the percentage of pentamer expressing cells. The compiled expression data of the frequency of Tax (E) and CMVpp65 (F) pentamer cells on either Tim-3+ or Tim-3- and PD-1+ or PD-1- CD8+ T cells from 8 subjects are shown in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0001030#pntd-0001030-g002" target="_blank">Figure 2</a> E and F. Statistical analyses comparing pooled responses were performed using the Mann-Whitney test.</p

Tim-3 expression on T cells in HTLV-1 infection.

<p>Graphs show the frequencies of co-expression of Tim-3 and PD-1 on (A) CD8+ (left), and (B) CD4+ (right), T cells as assessed by multiparametric flow cytometry from PBMCs derived 18 HTLV-1 seropositive (12 asymptomatic and 6 with diagnosis of HAM/TSP) infected subjects and 7 HTLV-1 seronegative healthy uninfected donors from our initial recruitment. Statistically significant differences are reported as p<0.05.</p

NEOTROPICAL CARNIVORES: a data set on carnivore distribution in the Neotropics

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data