Loss of Effector and Anti-Inflammatory Natural Killer T Lymphocyte Function in Pathogenic Simian Immunodeficiency Virus Infection

Namita Rout,Amitinder Kaur,David O'Connor,Simon Yue,Justin Greene,James G Else,R Paul Johnson,Mark A Exley,Daniel C Douek

doi:10.1371/journal.ppat.1002928

Abstract

Chronic immune activation is a key determinant of AIDS progression in HIV-infected humans and simian immunodeficiency virus (SIV)-infected macaques but is singularly absent in SIV-infected natural hosts. To investigate whether natural killer T (NKT) lymphocytes contribute to the differential modulation of immune activation in AIDS-susceptible and AIDS-resistant hosts, we compared NKT function in macaques and sooty mangabeys in the absence and presence of SIV infection. Cynomolgus macaques had significantly higher frequencies of circulating invariant NKT lymphocytes compared to both rhesus macaques and AIDS-resistant sooty mangabeys. Despite this difference, mangabey NKT lymphocytes were functionally distinct from both macaque species in their ability to secrete significantly more IFN-γ, IL-13, and IL-17 in response to CD1d/α-galactosylceramide stimulation. While NKT number and function remained intact in SIV-infected mangabeys, there was a profound reduction in NKT activation-induced, but not mitogen-induced, secretion of IFN-γ, IL-2, IL-10, and TGF-β in SIV-infected macaques. SIV-infected macaques also showed a selective decline in CD4+ NKT lymphocytes which correlated significantly with an increase in circulating activated memory CD4+ T lymphocytes. Macaques with lower pre-infection NKT frequencies showed a significantly greater CD4+ T lymphocyte decline post SIV infection. The disparate effect of SIV infection on NKT function in mangabeys and macaques could be a manifestation of their differential susceptibility to AIDS. Alternately, these data also raise the possibility that loss of anti-inflammatory NKT function promotes chronic immune activation in pathogenic SIV infection, while intact NKT function helps to protect natural hosts from developing immunodeficiency and aberrant immune activation.

Highlights

Absence of chronic immune activation is a key distinguishing feature that separates nonpathogenic simian immunodeficiency virus (SIV) infection in natural hosts from pathogenic lentiviral infection in HIV/SIV-infected humans and macaques [1]
These findings suggest that dysfunctional natural killer T (NKT) cells may promote increased immune activation in AIDS-susceptible hosts while intact effector and anti-inflammatory NKT cells could help to prevent immunodeficiency and increased immune activation in natural hosts
We previously reported that NKT lymphocytes in sooty mangabeys are unique in lacking expression of the CD4 molecule [23]

Summary

Introduction

Absence of chronic immune activation is a key distinguishing feature that separates nonpathogenic simian immunodeficiency virus (SIV) infection in natural hosts from pathogenic lentiviral infection in HIV/SIV-infected humans and macaques [1]. Classical NKT cells express an invariant TCRVa chain (Va14-Ja18 in mice and Va24-Ja18 in humans) paired to a restricted TCRVb repertoire [11] They express several markers of the NK lineage, have cytolytic activity, and display an activated or memory phenotype. NKT lymphocytes do not require prior sensitization and rapidly secrete copious amounts of both Th1 and Th2 cytokines, including IL-2, IFN-c and IL-4 upon antigen encounter. They modulate activation of other immune subsets including dendritic cells, NK cells, and B and T lymphocytes, and influence both innate and adaptive immunity [11,12,13]. As a result of their immunomodulatory and effector abilities, NKT lymphocytes can influence diverse functions, including tumor surveillance, anti-microbial defenses, and maintenance of self-tolerance [14,15]

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