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DC subset-specific induction of T cell responses upon antigen uptake via Fc? receptors in vivo.

ABSTRACT: Dendritic cells (DCs) are efficient antigen-presenting cells equipped with various cell surface receptors for the direct or indirect recognition of pathogenic microorganisms. Interestingly, not much is known about the specific expression pattern and function of the individual activating and inhibitory Fc? receptors (Fc?Rs) on splenic DC subsets in vivo and how they contribute to the initiation of T cell responses. By targeting antigens to select activating and the inhibitory Fc?R in vivo, we show that antigen uptake under steady-state conditions results in a short-term expansion of antigen-specific T cells, whereas under inflammatory conditions especially, the activating Fc?RIV is able to induce superior CD4⁺ and CD8⁺ T cell responses. Of note, this effect was independent of Fc?R intrinsic activating signaling pathways. Moreover, despite the expression of Fc?RIV on both conventional splenic DC subsets, the induction of CD8⁺ T cell responses was largely dependent on CD11c⁺CD8⁺ DCs, whereas CD11c⁺CD8^- DCs were critical for priming CD4⁺ T cell responses.

SUBMITTER: Lehmann CHK

PROVIDER: S-EPMC5413326 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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DC subset-specific induction of T cell responses upon antigen uptake via Fcγ receptors in vivo.

Lehmann Christian H K CHK Baranska Anna A Heidkamp Gordon F GF Heger Lukas L Neubert Kirsten K Lühr Jennifer J JJ Hoffmann Alana A Reimer Katharina C KC Brückner Christin C Beck Simone S Seeling Michaela M Kießling Melissa M Soulat Didier D Krug Anne B AB Ravetch Jeffrey V JV Leusen Jeanette H W JHW Nimmerjahn Falk F Dudziak Diana D

The Journal of experimental medicine 20170407 5

Dendritic cells (DCs) are efficient antigen-presenting cells equipped with various cell surface receptors for the direct or indirect recognition of pathogenic microorganisms. Interestingly, not much is known about the specific expression pattern and function of the individual activating and inhibitory Fcγ receptors (FcγRs) on splenic DC subsets in vivo and how they contribute to the initiation of T cell responses. By targeting antigens to select activating and the inhibitory FcγR in vivo, we sho ...[more]

PMID: 28389502

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Project description:Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)-dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance FcγR-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating FcγRIIIa and decrease binding to inhibitory FcγRIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell-mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms.

Dataset Information

DC subset-specific induction of T cell responses upon antigen uptake via Fc? receptors in vivo.

Publications

DC subset-specific induction of T cell responses upon antigen uptake via Fcγ receptors in vivo.

Similar Datasets

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