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ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function.

ABSTRACT: The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

SUBMITTER: D'Amico S

PROVIDER: S-EPMC8669763 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bw4 homozygosity in human leukocyte antigen class B alleles has been associated with a delayed acquired immunodeficiency syndrome (AIDS) development and better control of human immunodeficiency virus type 1 (HIV-1) viral load (VL) than Bw6 homozygosity. Efficient CD8 T cell and natural killer (NK) cell functions have been described to restrain HIV-1 replication. However, the role of KIR3DL1 expression on these cells was not assessed in Bw4-homozygous participants infected with HIV-1 CRF01_A/E subtype, currently the most prevalent subtype in China. Here, we found that the frequency of KIR3DL1-expressing CD8 T cells of individuals homozygous for Bw6 [1.53% (0-4.56%)] was associated with a higher VL set point (Spearman rs?=?0.59, P?=?0.019), but this frequency of KIR3DL1+CD8+ T cells [1.37% (0.04-6.14%)] was inversely correlated with CD4 T-cell count in individuals homozygous for Bw4 (rs?=?-0.59, P?=?0.011). Moreover, CD69 and Ki67 were more frequently expressed in KIR3DL1-CD8+ T cells in individuals homozygous for Bw4 than Bw6 (P?=?0.046 for CD69; P?=?0.044 for Ki67), although these molecules were less frequently expressed in KIR3DL1+CD8+ T cells than in KIR3DL1-CD8+ T cells in both groups (all P?<?0.05). KIR3DL1-CD8+ T cells have stronger p24-specific CD8+ T-cell responses secreting IFN-? and CD107a than KIR3DL1+CD8+ T cells in both groups (all P?<?0.05). Thus, KIR3DL1 expression on CD8 T cells were associated with the loss of multiple functions. Interestingly, CD69+NK cells lacking KIR3DL1 expression were inversely correlated with HIV-1 VL set point in Bw4-homozygous individuals (rs?=?-0.52, P?=?0.035). Therefore, KIR3DL1-CD8+ T cells with strong early activation and proliferation may, together with KIR3DL1-CD69+NK cells, play a protective role during acute/early HIV infection in individuals homozygous for Bw4. These findings highlight the superior functions of KIR3DL1-CD8+ T cells and KIR3DL1-CD69+NK cells being a potential factor contributing to delayed disease progression in the early stages of HIV-1 infection.

Project description:BackgroundHLA-E interaction with inhibitory receptor, NKG2A attenuates NK-mediated cytotoxicity. NKG2A overexpression by SARS-CoV-2 exhausts NK cells function, whereas virus-induced down-regulation of MHC-Ia reduces its derived-leader sequence peptide levels required for proper binding of HLA-E to NKG2A. This leads HLA-E to become more complex with viral antigens and delivers them to CD8+ T cells, which facilitates cytolysis of infected cells. Now, the fact that alleles of HLA-E have different levels of expression and affinity for MHC Ia-derived peptide raises the question of whether HLA-E polymorphisms affect susceptibility to COVID-19 or its severity.Methods104 COVID-19 convalescent plasma donors with/without history of hospitalization and 18 blood donors with asymptomatic COVID-19, all were positive for anti-SARS-CoV-2 IgG antibody as well as a group of healthy control including 68 blood donors with negative antibody were subjected to HLA-E genotyping. As a privilege, individuals hadn't been vaccinated against COVID-19 and therefore naturally exposed to the SARS-CoV-2.ResultsThe absence of HLA-E*01:03 allele significantly decreases the odds of susceptibility to SARS-CoV-2 infection [p = 0.044; OR (95 %CI) = 0.530 (0.286 - 0.983)], suggesting that HLA-E*01:01 + HLA-E*01:01 genotype favors more protection against SARS-CoV-2 infection. HLA-E*01:03 + HLA-E*01:03 genotype was also significantly associated with more severe COVID-19 [p = 0.020; 2.606 (1.163 - 5.844) CONCLUSION: Here, our observation about lower susceptibility of HLA-E*01:01 + HLA-E*01:01 genotype to COVID-19 could be clinical evidence in support of some previous studies suggesting that the lower affinity of HLA-E*01:01 to peptides derived from the leader sequence of MHC class Ia may instead shift its binding to virus-derived peptides, which then facilitates target recognition by restricted conventional CD8+ T cells and leads to efficient cytolysis. On the other hand, according to other studies, less reactivity of HLA-E*01:01 with NKG2A abrogates NK cells or T cells inhibition, which may also lead to a greater cytotoxicity against SARS-CoV-2 infected cells compared to HLA-E*01:03. Taken together given HLA-E polymorphisms, the data presented here may be useful in identifying more vulnerable individuals to COVID-19 for better care and management. Especially since along with other risk factors in patients, having HLA-E*01:03 + HLA-E*01:03 genotype may also be associated with the possibility of severe cases of the disease.

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ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function.

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