Negative Checkpoint Regulatory Molecule 2B4 (CD244) Upregulation Is Associated with Invariant Natural Killer T Cell Alterations and Human Immunodeficiency Virus Disease Progression.

Fareed Ahmad,Yean K Yong,Gerrit Ahrenstorf,Adeeba Kamarulzaman,Marie Larsson,Roland Jacobs,Reinhold E Schmidt,Hong Y Tan,Esaki M Shankar,Abdul W Ansari

doi:10.3389/fimmu.2017.00338

Abstract

The CD1d-restricted invariant natural killer T (iNKT) cells are implicated in innate immune responses against human immunodeficiency virus (HIV). However, the determinants of cellular dysfunction across the iNKT cells subsets are seldom defined in HIV disease. Herein, we provide evidence for the involvement of the negative checkpoint regulator (NCR) 2B4 in iNKT cell alteration in a well-defined cohort of HIV-seropositive anti-retroviral therapy (ART) naïve, ART-treated, and elite controllers (ECs). We report on exaggerated 2B4 expression on iNKT cells of HIV-infected treatment-naïve individuals. In sharp contrast to CD4−iNKT cells, 2B4 expression was significantly higher on CD4+ iNKT cell subset. Notably, an increased level of 2B4 on iNKT cells was strongly correlated with parameters associated with HIV disease progression. Further, iNKT cells from ART-naïve individuals were defective in their ability to produce intracellular IFN-γ. Together, our results suggest that the levels of 2B4 expression and the downstream co-inhibitory signaling events may contribute to impaired iNKT cell responses.

Highlights

Invariant natural killer T cells are a unique subset of T lymphocyte that bridges innate and adaptive immune responses [1]
CD4+ Invariant natural killer T (iNKT) Cell Subset Was Preferentially Lost from the Circulation of human immunodeficiency virus (HIV)-Positive Treatment-Naïve Patients, and anti- retroviral therapy (ART) Failed to Restore CD4+ iNKT Cell Frequency
We report for the first time, the relationship between the levels of 2B4, a co-inhibitory molecule, and their impact on iNKT cell dysfunction in HIV infection

Summary

Introduction

Invariant natural killer T (iNKT) cells are a unique subset of T lymphocyte that bridges innate and adaptive immune responses [1]. In addition to immune regulation, iNKT cell role is implicated in several viral infections [2]. INKT cells express invariant TCR Vα24 and Vβ11 chain, and NK cell markers such as CD161 and NKG2D [1]. INKT cells rapidly produce large amounts of both IFN-γ (Th1) and IL-4 (Th2) cytokines to regulate host immune responses. INKT cells can be classified into CD4− (Th1cytokine-expressing) and CD4+ (Th1 and Th2 cytokine-producing) subsets. Evidence suggests that CD4+ and CD4−iNKT cell homeostasis significantly impact the functional outcome of immune responses in the host [6, 7]

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