Th1 and Th17 proinflammatory profile characterizes invariant natural killer T cells in virologically suppressed HIV+ patients with low CD4+/CD8+ ratio.

Sara De Biasi,Vanni Borghi,Marcello Pinti,Cristina Mussini,Elena Bianchini,Andrea Cossarizza,Milena Nasi,Gianluca Carnevale,Lara Gibellini,Giovanni Guaraldi,Margherita Digaetano

doi:10.1097/qad.0000000000001247

Abstract

Scanty data exist on the phenotype and functionality of invariant natural killer T (iNKT) cells in HIV-infected (HIV+) patients. By flow cytometry, we studied iNKT cells from 54 HIV+ patients who started combined antiretroviral therapy and had undetectable viral load for more than 1 year. Twenty-five maintained a CD4/CD8 ratio less than 0.4, whereas 29 reached a ratio more than 1.1; 32 age-matched and sex-matched patients were healthy controls (CTR). Patients with low ratio had lower percentage of CD4 iNKT cells compared with patients with high ratio and higher CD8 iNKT cell percentage; double-negative iNKT cells were lower in HIV+ patients compared with CTR. Patients with low ratio had higher percentage of CD4 and double-negative iNKT cells expressing CD38 and HLA-DR compared with patients with high ratio. CD4 iNKT cells expressing PD-1 were higher in patients with CD4/CD8 ratio less than 0.4, whereas double-negative iNKT cells expressing PD-1 were lower compared with patients with ratio more than 1.1. Patients with low ratio had higher CD4 iNKT cells producing IL-17, CD8 iNKT cells producing IFN-γ, TNF-α or IFN-γ and TNF-α, and double-negative iNKT cells producing IL-17 or IL-17 and IFN-γ compared with CTR. Activated CD4 (or CD8) T cells correlated with activated CD4 (or CD8) iNKT cells, as well as the percentages of CD4 (or CD8) T cells expressing PD-1 was correlated to that of CD4 (or CD8) iNKT cells expressing PD-1. Low CD4/CD8 ratio despite effective combined antiretroviral therapy is associated with altered iNKT cell subsets, enhanced activation, and prominent Th1/Th17 proinflammatory profile.

Highlights

Scanty data exist on the phenotype and functionality of invariant natural killer T cells in HIV-infected (HIVþ) patients
Polychromatic flow cytometry To identify circulating invariant natural killer T (iNKT) cells, whose percentage in peripheral blood is typically less than 1%, and in HIVþ patients even less, it is mandatory to acquire a huge number of cells [20,21]
Production of cytokines by invariant natural killer T cells after in-vitro stimulation We investigated the ability of iNKT cells to produce simultaneously different cytokines

Summary

Introduction

Scanty data exist on the phenotype and functionality of invariant natural killer T (iNKT) cells in HIV-infected (HIVþ) patients. The mechanisms at the basis of the failure of immune recovery in these patients are not well understood, but likely include those involved in the regulation of T-cell homeostasis Among such mechanisms, those based upon invariant natural killer T (iNKT) cells have never been investigated in detail. INKT cells are innate-like lymphocytes that recognize glycolipid antigens presented by major histocompatibility complex class-I-related glycoprotein CD1d and exert important immunoregulatory functions [3,4,5]. These cells represent about 0.01–1.0% of peripheral blood mononuclear cells (PBMCs) and are characterized by the presence of a semi-invariant T-cell receptor (iTCR), formed by a Va24Ja18 a-chain coupled with a Vb11 b-chain [6]. This rare population rapidly produces proinflammatory and/or antiinflammatory cytokines able to orchestrate innate immunity through the recruitment and activation of different types of effector cells (NK cells and dendritic cells) as well as B and T cells [7,8,9,10,11]. iNKT cells can be divided into different subsets on the basis of the expression of CD4þ and CD8þ; in turn, each subset is functionally distinct: CD4þ subset mainly produces Th2 cytokines, whereas CD8þ and CD4ÀCD8À (doublenegative) iNKT cells are characterized by the production of Th1 cytokine and a strong cytolytic activity [12]

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Results

Conclusion