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Dendritic cells can prime anti-tumor CD8⁺ T cell responses through major histocompatibility complex cross-dressing.

ABSTRACT: Antigen cross-presentation, wherein dendritic cells (DCs) present exogenous antigen on major histocompatibility class I (MHC-I) molecules, is considered the primary mechanism by which DCs initiate tumor-specific CD8⁺ T cell responses. Here, we demonstrate that MHC-I cross-dressing, an antigen presentation pathway in which DCs acquire and display intact tumor-derived peptide:MHC-I molecules, is also important in orchestrating anti-tumor immunity. Cancer cell MHC-I expression was required for optimal CD8⁺ T cell activation in two subcutaneous tumor models. In vivo acquisition of tumor-derived peptide:MHC-I molecules by DCs was sufficient to induce antigen-specific CD8⁺ T cell priming. Transfer of tumor-derived human leukocyte antigen (HLA) molecules to myeloid cells was detected in vitro and in human tumor xenografts. In conclusion, MHC-I cross-dressing is crucial for anti-tumor CD8⁺ T cell priming by DCs. In addition to quantitatively enhancing tumor antigen presentation, MHC cross-dressing might also enable DCs to more faithfully and efficiently mirror the cancer cell peptidome.

SUBMITTER: MacNabb BW

PROVIDER: S-EPMC9883788 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Dendritic cells can prime anti-tumor CD8<sup>+</sup> T cell responses through major histocompatibility complex cross-dressing.

MacNabb Brendan W BW Tumuluru Sravya S Chen Xiufen X Godfrey James J Kasal Darshan N DN Yu Jovian J Jongsma Marlieke L M MLM Spaapen Robbert M RM Kline Douglas E DE Kline Justin J

Immunity 20220525 6

Antigen cross-presentation, wherein dendritic cells (DCs) present exogenous antigen on major histocompatibility class I (MHC-I) molecules, is considered the primary mechanism by which DCs initiate tumor-specific CD8<sup>+</sup> T cell responses. Here, we demonstrate that MHC-I cross-dressing, an antigen presentation pathway in which DCs acquire and display intact tumor-derived peptide:MHC-I molecules, is also important in orchestrating anti-tumor immunity. Cancer cell MHC-I expression was requir ...[more]

PMID: 35617964

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Project description:Human cytomegalovirus (HCMV) persistently infects 40-90% of the human population but in the face of a normal immune system, viral spread and dissemination are efficiently controlled thus preventing clinically signs and disease. HCMV-infected hosts produce a remarkably large amount of HCMV-specific CD4+ and CD8+ T cells that can even reach 20-50% of total T memory cells in the elderly. How HCMV may elicit such large and long-lasting T-cell responses in the absence of detectable viremia has not been elucidated yet. Additionally, HCMV is known to encode several gene products that potently inhibit T-cell recognition of infected cells. The best characterized are the four immune evasive US2, US3, US6, and US11 genes that by different mechanisms account for major histocompatibility complex (MHC) class I and class II degradation and intracellular retention in infected cells. By infecting M1 and M2 human macrophages (Mφ) with the wild-type HCMV strain TB40E or a mutant virus deleted of the four immune evasive genes US2, US3, US6, and US11, we demonstrated that human Mφ counteract the inhibitory potential of the US2-11 genes and remain capable to present peptides via MHC class I and class II molecules. Moreover, by sorting the infected and bystander cells, we provide evidence that both infected and bystander Mφ contribute to antigen presentation to CD4+ and CD8+ T cells. The T cells responding to TB40E-infected Mφ show markers of the T effector memory compartment, produce interferon-γ, and express the lytic granule marker CD107a on the cell surface, thus mirroring the HCMV-specific T cells present in healthy seropositive individuals. All together, our findings reveal that human Mφ escape inhibition of MHC-dependent antigen presentation by HCMV and continue to support T cell proliferation and activation after HCMV infection. Taking into account that Mφ are natural targets of HCMV infection and a site of viral reactivation from latency, our findings support the hypothesis that Mφ play crucial roles for the lifelong maintenance and expansion of HCMV-committed T cells in the human host.

Dataset Information

Dendritic cells can prime anti-tumor CD8⁺ T cell responses through major histocompatibility complex cross-dressing.

Publications

Dendritic cells can prime anti-tumor CD8<sup>+</sup> T cell responses through major histocompatibility complex cross-dressing.

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OmicsDI is part of the ELIXIR infrastructure

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Dendritic cells can prime anti-tumor CD8+ T cell responses through major histocompatibility complex cross-dressing.

Publications

Dendritic cells can prime anti-tumor CD8<sup>+</sup> T cell responses through major histocompatibility complex cross-dressing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dendritic cells can prime anti-tumor CD8⁺ T cell responses through major histocompatibility complex cross-dressing.