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Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques

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Tuyishime, M; Spreng, RL; Hueber, B; Nohara, J; Goodman, D; Chan, C; Barfield, R; Beck, WE; Jha, S; Asdell, S; Wiehe, K; He, MM; Conley, HE ...
Published in: Frontiers in Immunology
January 1, 2023

Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials.

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Published In

Frontiers in Immunology

DOI

EISSN

1664-3224

Publication Date

January 1, 2023

Volume

14

Related Subject Headings

  • 3204 Immunology
  • 3105 Genetics
  • 3101 Biochemistry and cell biology
  • 1108 Medical Microbiology
  • 1107 Immunology
 

Citation

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MLA
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Tuyishime, M., Spreng, R. L., Hueber, B., Nohara, J., Goodman, D., Chan, C., … Ferrari, G. (2023). Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques. In Frontiers in Immunology (Vol. 14). https://doi.org/10.3389/fimmu.2023.1260377
Tuyishime, M., R. L. Spreng, B. Hueber, J. Nohara, D. Goodman, C. Chan, R. Barfield, et al. “Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques.” In Frontiers in Immunology, Vol. 14, 2023. https://doi.org/10.3389/fimmu.2023.1260377.
Tuyishime M, Spreng RL, Hueber B, Nohara J, Goodman D, Chan C, et al. Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques. In: Frontiers in Immunology. 2023.
Tuyishime, M., et al. “Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques.” Frontiers in Immunology, vol. 14, 2023. Scopus, doi:10.3389/fimmu.2023.1260377.
Tuyishime M, Spreng RL, Hueber B, Nohara J, Goodman D, Chan C, Barfield R, Beck WE, Jha S, Asdell S, Wiehe K, He MM, Easterhoff D, Conley HE, Hoxie T, Gurley T, Jones C, Adhikary ND, Villinger F, Thomas R, Denny TN, Moody MA, Tomaras GD, Pollara J, Reeves RK, Ferrari G. Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques. Frontiers in Immunology. 2023.

Published In

Frontiers in Immunology

DOI

EISSN

1664-3224

Publication Date

January 1, 2023

Volume

14

Related Subject Headings

  • 3204 Immunology
  • 3105 Genetics
  • 3101 Biochemistry and cell biology
  • 1108 Medical Microbiology
  • 1107 Immunology