Paucity of CD4+ Natural Killer T (NKT) Lymphocytes in Sooty Mangabeys Is Associated with Lack of NKT Cell Depletion after SIV Infection

Namita Rout,Simon Yue,James G Else,Amitinder Kaur,Mark A Exley,Michelle Connole

doi:10.1371/journal.pone.0009787

Abstract

Lack of chronic immune activation in the presence of persistent viremia is a key feature that distinguishes nonpathogenic simian immunodeficiency virus (SIV) infection in natural hosts from pathogenic SIV and HIV infection. To elucidate novel mechanisms downmodulating immune activation in natural hosts of SIV infection, we investigated natural killer T (NKT) lymphocytes in sooty mangabeys. NKT lymphocytes are a potent immunoregulatory arm of the innate immune system that recognize glycolipid antigens presented on the nonpolymorphic MHC-class I-like CD1d molecules. In a cross-sectional analysis of 50 SIV-negative and 50 naturally SIV-infected sooty mangabeys, ligand α-galactosylceramide loaded CD1d tetramers co-staining with Vα24-positive invariant NKT lymphocytes were detected at frequencies ≥0.002% of circulating T lymphocytes in approximately half of the animals. In contrast to published reports in Asian macaques, sooty mangabey NKT lymphocytes consisted of CD8+ and CD4/CD8 double-negative T lymphocytes that were CXCR3-positive and CCR5-negative suggesting that they trafficked to sites of inflammation without being susceptible to SIV infection. Consistent with these findings, there was no difference in the frequency or phenotype of NKT lymphocytes between SIV-negative and SIV-infected sooty mangabeys. On stimulation with α-galactosylceramide loaded on human CD1d molecules, sooty mangabey NKT lymphocytes underwent degranulation and secreted IFN-γ, TNF-α, IL-2, IL-13, and IL-10, indicating the presence of both effector and immunoregulatory functional capabilities. The unique absence of CD4+ NKT lymphocytes in sooty mangabeys, combined with their IL-10 cytokine-secreting ability and preservation following SIV infection, raises the possibility that NKT lymphocytes might play a role in downmodulating immune activation in SIV-infected sooty mangabeys.

Highlights

While persistent immune activation is a strong prognosticator of disease progression in HIV-infected humans and simian immunodeficiency virus (SIV)-infected Asian macaques, it is singularly lacking in non-progressive infection in natural hosts of SIV such as sooty mangabeys and African green monkeys [1,2,3,4]
Identification of Natural Killer T (NKT) lymphocytes in sooty mangabeys The majority of human CD1d-reactive NKT lymphocytes express the invariant Va24-Ja18 TCR a-chain paired with the Vb11 TCR b-chain and are identified by flow cytometric detection of Va24 TCR-positive T lymphocytes that either bind to the 6B11 mAb directed against the invariant CDR3 region of the TCR a-chain [55], or that bind to human CD1d tetramers loaded with ligand a-galactosylceramide (a-GalCer) or its analog, PBS-57 [56,57]
A small subset of Va24+CD1d tetramers (CD1d TM)+ cells were not 6B11+ (Figure 1B bottom panel), indicating the presence of a minor population of non-invariant NKT lymphocytes in sooty mangabeys, as have been reported in humans

Summary

Introduction

While persistent immune activation is a strong prognosticator of disease progression in HIV-infected humans and SIV-infected Asian macaques, it is singularly lacking in non-progressive infection in natural hosts of SIV such as sooty mangabeys and African green monkeys [1,2,3,4]. Immune activation is observed during acute SIV infection in sooty mangabeys and African green monkeys, but it is rapidly down-regulated to pre-SIV infection levels [6,7,8,9,10]. The magnitude of SIV-specific T lymphocyte responses in sooty mangabeys during acute and chronic SIV infection is comparable to that in rhesus macaques [9,17,18] and differences in the adaptive immune response to SIV are unlikely to be responsible for the differential immune activation of pathogenic and nonpathogenic SIV infection. The rapid activation of multiple pro-inflammatory cytokines and chemokines in acute HIV and SIV infection point to the early innate immune response as an important determinant of immune activation [9,19]

Methods

Results

Conclusion