Abstract
CD8+ T cell response is important in the response to viral infections; this response though is regulated by inhibitory receptors. Expression of inhibitory receptors has been positively correlated with CD8+ T cell exhaustion; the consequent effect of simultaneous blockade of these inhibitory receptors on CD8+ T cell response in viral infections have been studied, however, the role of individual blockade of receptor-ligand pair is unclear. 2B4/CD48 interaction is involved in CD8+T cell regulation, its signal transducer SAP (signaling lymphocyte activation molecule (SLAM)-associated protein) is required for stimulatory function of 2B4/CD244 on lymphocytes hence, we analyzed 2B4/CD244 (natural killer cell receptor) and SAP (signaling lymphocyte activation molecule(SLAM)-associated protein) on total CD8+ and HTLV-1 specific CD8+T cells in HTLV-1 infection and the effect of blockade of interaction with ligand CD48 on HTLV-1 specific CD8+ T cell function. We observed a high expression of 2B4/CD244 on CD8+ T cells relative to uninfected and further upregulation on HTLV-1 specific CD8+ T cells. 2B4+ CD8+ T cells exhibited more of an effector and terminally differentiated memory phenotype. Blockade of 2B4/CD48 interaction resulted in improvement in function via perforin expression and degranulation as measured by CD107a surface mobilization on HTLV-1 specific CD8+ T cells. In the light of these findings, we thus propose an inhibitory role for 2B4/CD48 interaction on CD8+T cell function.
Highlights
The Human T-lymphotropic virus type 1 (HTLV-1) is implicated in the highly aggressive malignancy, adult T-cell leukemia/lymphoma (ATLL)
Maturational Phenotype of CD8+2B4+ T Cells To determine the pattern of expression of 2B4 on CD8+T cells differentiation in CD8+ T cells from HTLV-1 infected, we examined 2B4 expression relative to CD45RA and CCR7 coexpression. 2B4 was present mainly in the naıve, effector and terminally differentiated memory groups, with a preference for terminally differentiated (CD45RA+CCR72 mean 87% 69.9%) and effector memory (CD45RA-CCR7-mean 7.8% 65.4) compartments
2B4+CD8+T cells were significantly higher in uninfected healthy donors (HD) compared to ATLL and asymptomatic carriers (ACs) (ATLL 0.5960.53; AC 0.3860.38; HD 8.2267.2; p,0.05) possibly suggesting ongoing activation in response to exposure to viral infection
Summary
The Human T-lymphotropic virus type 1 (HTLV-1) is implicated in the highly aggressive malignancy, adult T-cell leukemia/lymphoma (ATLL). Constant antigenic stimulation due to chronic hyper-antigenemia in the context of viral persistence induces T-cell exhaustion, a state characterized by impaired CTL function [11,12,13,14] This can be attributed in part to the presence of co-inhibitory markers involved in modulating T-cell response to infection [15,16]. In mouse models of chronic viral infection with lymphocytic choriomeningitic virus (LCMV) infection, CTLs demonstrated increased expression of co-inhibitory receptors and reduced cytolytic function as has been reported for Hepatitis B virus (HBV), Hepatitis C virus (HCV) and Human immunodeficiency virus infections (HIV-1) in humans. The interaction of these receptors with their ligands results in reduced T cell function and ligand blockade improved CTL function in the different viral infections [11,14,16,17,18,19]
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