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Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function.

ABSTRACT: When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8+ T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferentially bind CD8 and to a majority of blood-derived CD8+ T cells via a CD8-dependent binding mode. Further functional studies reveal that peptide-deficient conformers of HLA-B*35:01 do not directly activate CD8+ T cells, but accumulate at the immunological synapse in antigen-induced responses, and enhance cognate peptide-induced cell adhesion and CD8+ T cell activation. Together, these findings indicate that HLA-I peptide occupancy influences CD8 binding affinity, and reveal a new set of regulators of CD8+ T cell activation, mediated by the binding of empty HLA-I to CD8.

SUBMITTER: Geng J

PROVIDER: S-EPMC5990358 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Empty conformers of HLA-B preferentially bind CD8 and regulate CD8<sup>+</sup> T cell function.

Geng Jie J Altman John D JD Krishnakumar Sujatha S Raghavan Malini M

eLife 20180509

When complexed with antigenic peptides, human leukocyte antigen (HLA) class I (HLA-I) molecules initiate CD8<sup>+</sup> T cell responses via interaction with the T cell receptor (TCR) and co-receptor CD8. Peptides are generally critical for the stable cell surface expression of HLA-I molecules. However, for HLA-I alleles such as HLA-B*35:01, peptide-deficient (empty) heterodimers are thermostable and detectable on the cell surface. Additionally, peptide-deficient HLA-B*35:01 tetramers preferent ...[more]

PMID: 29741477

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Project description:BackgroundNorepinephrine (NE) is one of the primary catecholamines of the sympathetic nervous system released during a stress response and plays an important role in modulating immune function. NE binds to the adrenergic receptors on immune cells, including T cells, resulting in either suppressed or enhanced function depending on the type of cell, activation status of the cell, duration of NE exposure and concentration of NE. Here, we aim to analyze the effects of NE on the functionality of naïve (Tn), central memory (Tcm) and effector memory (Tem) CD8 T cells.MethodsWe isolated CD8 T cell subsets from healthy human adults and treated cells in vitro with NE (1×10(-6)M) for 16h; we then stimulated NE treated and untreated CD8 T cell subsets with antibodies for CD3 and CD28 for 24 and 72h. We assessed the level of beta-2 adrenergic receptor (ADRB2) expression in these cells as well as global gene expression changes in NE treated Tcm cells by microarray analysis. Altered expressed genes after NE treatment were identified and further confirmed by RT-qPCR, and by ELISA for protein changes. We further determined whether the observed NE effects on memory CD8 T cells are mediated by ADRB2 using specific adrenergic receptor agonist and antagonists. Finally, we examined the levels of mRNA and protein of the NE-induced genes in healthy adults with high serum levels of NE (>150pg/mL) compared to low levels (<150pg/mL).ResultsWe found that memory (Tcm and Tem) CD8 T cells expressed a significantly higher level of ADRB2 compared to naïve cells. Consequently, memory CD8 T cells were significantly more sensitive than naïve cells to NE induced changes in gene expressions in vitro. Global gene expression analysis revealed that NE induced an elevated expression of inflammatory cytokines and chemokines in resting and activated memory CD8 T cells in addition to a reduced expression of growth-related cytokines. The effects of NE on memory CD8 T cells were primarily mediated by ADRB2 as confirmed by the adrenergic receptor agonist and antagonist assays. Finally, individuals with high serum levels of NE had similar elevated gene expressions observed in vitro compared to the low NE group.ConclusionsOur results demonstrate that NE preferentially modulates the functions of memory CD8 T cells by inducing inflammatory cytokine production and reducing activation-induced memory CD8 T cell expansion.

Project description:Recruitment and activation of CD8 T cells occur through specific triggering of T cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the generated trimeric TCR-peptide:HLA complex, the molecular binding affinities between peptide and HLA, and between TCR and peptide:HLA both impact T cell functional outcomes. However, how their individual and combined effects modulate immunogenicity and overall T cell responsiveness has not been investigated systematically. Here, we established two panels of human tumor peptide variants differing in their affinity to HLA. For precise characterization, we developed the "blue peptide assay", an upgraded cell-based approach to measure the peptide:HLA affinity. These peptide variants were then used to investigate the cross-reactivity of tumor antigen-specific CD8 T cell clonotypes derived from blood of cancer patients after vaccination with either the native or an affinity-optimized Melan-A/MART-1 epitope, or isolated from tumor infiltrated lymph nodes (TILNs). Vaccines containing the native tumor epitope generated T cells with better functionality, and superior cross-reactivity against potential low affinity escape epitopes, as compared to T cells induced by vaccines containing an HLA affinity-optimized epitope. Comparatively, Melan-A/MART-1-specific TILN cells displayed functional and cross-reactive profiles that were heterogeneous and clonotype-dependent. Finally, we took advantage of a collection of T cells expressing affinity-optimized NY-ESO-1-specific TCRs to interrogate the individual and combined impact of peptide:HLA and TCR-pHLA affinities on overall CD8 T cell responses. We found profound and distinct effects of both biophysical parameters, with additive contributions and absence of hierarchical dominance. Altogether, the biological impact of peptide:HLA and TCR-pHLA affinities on T cell responses was carefully dissected in two antigenic systems, frequently targeted in human cancer immunotherapy. Our technology and stepwise comparison open new insights into the rational design and selection of vaccine-associated tumor-specific epitopes and highlight the functional and cross-reactivity profiles that endow T cells with best tumor control capacity.

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Empty conformers of HLA-B preferentially bind CD8 and regulate CD8+ T cell function.

Publications

Empty conformers of HLA-B preferentially bind CD8 and regulate CD8<sup>+</sup> T cell function.

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