Abstract
Natural Killer (NK) cell responses to HIV-infected CD4 T cells (iCD4) depend on the integration of signals received through inhibitory (iNKR) and activating NK receptors (aNKR). iCD4 activate NK cells to inhibit HIV replication. HIV infection-dependent changes in the human leukocyte antigen (HLA) ligands for iNKR on iCD4 are well documented. By contrast, less is known regarding the HIV infection related changes in ligands for aNKR on iCD4. We examined the aNKR ligand profiles HIV p24+ HIV iCD4s that maintained cell surface CD4 (iCD4+), did not maintain CD4 (iCD4−) and uninfected CD4 (unCD4) T cells for expression of unique long (UL)-16 binding proteins-1 (ULBP-1), ULBP-2/5/6, ULBP-3, major histocompatibility complex (MHC) class 1-related (MIC)-A, MIC-B, CD48, CD80, CD86, CD112, CD155, Intercellular adhesion molecule (ICAM)-1, ICAM-2, HLA-E, HLA-F, HLA-A2, HLA-C, and the ligands to NKp30, NKp44, NKp46, and killer immunoglobulin-like receptor 3DS1 (KIR3DS1) by flow cytometry on CD4 T cells from 17 HIV-1 seronegative donors activated and infected with HIV. iCD4+ cells had higher expression of aNKR ligands than did unCD4. However, the expression of aNKR ligands on iCD4 where CD4 was downregulated (iCD4−) was similar to (ULBP-1, ULBP-2/5/6, ULBP-3, MIC-A, CD48, CD80, CD86 and CD155) or significantly lower than (MIC-B, CD112 and ICAM-2) what was observed on unCD4. Thus, HIV infection can be associated with increased expression of aNKR ligands or either baseline or lower than baseline levels of aNKR ligands, concomitantly with the HIV-mediated downregulation of cell surface CD4 on infected cells.
Highlights
Natural Killer (NK) cells are innate immune cells that mediate cytotoxic responses to stressed, virally-infected, and transformed cells [1]
We report that elucidating HIV-induced regulation of the activating NK receptors (aNKR) ligand expression profile on infected cells would infection is associated with significant changes to the expression profiles of ligands to aNKRs
The results presented here add to this body of work by including aNKR ligands not previously studied, including CD112 and Intercellular adhesion molecule (ICAM)-2
Summary
Natural Killer (NK) cells are innate immune cells that mediate cytotoxic responses to stressed, virally-infected, and transformed cells [1]. NK cells can lyse target cells directly through the production of granzyme and perforin, or indirectly through antibody (Ab)-dependent mechanisms, through the production of cytokines and chemokines, and through activation of adaptive immune cells [2,3,4]. The induction and potency of these responses depend on the activation state of the NK cell, which is regulated by signals transmitted through both activating and inhibitory NK cell receptors (aNKR and iNKRs) [4,5]. When signals from iNKR are interrupted, NK cell activation can occur if target cells express ligands to aNKR [1,4,5,7]. In vivo most cells co-express variable combinations of ligands to both NKR types and NK cell activation will depend on the integration of the number and strength of all activating and inhibitory signals transmitted
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