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Primed macrophages gain long-term specific memory to reject allogeneic tissues in mice

Cellular & Molecular Immunology volume 18, pages 1079–1081 (2021)Cite this article

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It is believed that the adaptive immune system responds to nonself according to its specificity and memory properties, whereas the innate immune system lacks adaptive characteristics. The specificity of the adaptive immune response is based on irreversible changes in the DNA sequence by retroposons encoding site-specific recombinases, which generate unlimited numbers of receptors to allow B lymphocytes and T lymphocytes to specifically recognize antigens. Recent studies have shown that innate myeloid cells can engage in allogeneic recognition with specificity and respond to subsequent triggers more strongly than the primary response, a process revealing the immune memory property termed “trained immunity”.1,2 After encountering allogeneic splenocytes 1 or 4 weeks prior to the experiment, monocytes of lymphocyte-deficient Rag2-deficient mice cause a delayed-type hypersensitivity-like reaction, suggesting that this type of allogeneic antigen recognition is manifested in memory responses.3 Liu et al. showed that macrophages from mice primed with allogeneic cells readily recognized and rejected allogeneic cells.4 Importantly, Chu et al. recently demonstrated that allogeneic antigen-primed macrophages alone acutely rejected allogeneic skin grafts with specificity after adoptive transfer of these cells into MHC-matched immunodeficient mice.5 In the present study, we found that macrophages primed with the help of CD4+ T cells in the priming stage could reject allogeneic cells and skin grafts due to long-term memory properties (at least 4 months) in a mouse model in which immunodeficient mice received adoptive transfer of primed macrophages. These results revealed that primed macrophages gained long-term memory features to specifically mediate allograft rejection.

Do primed macrophages have the ability via memory to reject skin tissue allografts? The primed PEMs were sorted from naive or B6 splenocyte-immunized BALB/c mice and adoptively transferred into MHC-matched SCID mice. These SCID mice were subsequently grafted with either B6 or third-party FvB skin tissues, as shown in Fig. 1d. SCID mice that received naive PEMs received allogeneic B6 skin grafts and did not show evidence of rejection for more than 100 days. However, SCID mice that received B6 cell-primed PEMs efficiently rejected priming donor B6 skin grafts within 40 days, while they rejected third-party FvB skin grafts in a significantly delayed manner, regardless of whether the PEMs were isolated from BALB/c mice immunized with B6 splenocytes 10 days or 120 days ago (P < 0.01, Fig. 1e, f). Therefore, primed macrophages could somehow specifically reject allogeneic skin grafts, as reported previously.5 Importantly, the primed PEMs isolated from BALB/c mice that were immunized with B6 splenocytes 120 days ago could also efficiently reject priming donor B6 skin grafts after their adoptive transfer into MHC-matched SCID mice similar to primed PEMs isolated from BALB/c mice that were immunized with B6 splenocytes 10 days ago. These data indicated that the ability of the primed macrophages to specifically reject allogeneic skin grafts could be maintained for at least 120 days in mice after immunization.

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Acknowledgements

The authors thank Dr. Zhanfeng Liang for his kind review of the manuscript and Qing Meng for her expert technical assistance. This work was supported by grants from the National Key R&D Program of China (2017YFA0105002, 2017YFA0104402, Y.Z.), the Chinese Government 13th Five-Year Plan (2017ZX10201101), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030301, Y.Z.), the National Natural Science Foundation for General and Key Programs (C81530049, C81130055, C31470860, U1738111, Y.Z.), and the Fundamental Research Funds for the Central Universities (2018-JYBZZ-XJSJJ004, Z.C.).

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  1. These authors contributed equally: Zhulang Chu, Chang Feng, Chenming Sun

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China

    Zhulang Chu, Chang Feng, Chenming Sun, Yanan Xu & Yong Zhao

  2. Department of Pathology, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China

    Zhulang Chu

  3. University of Chinese Academy of Sciences, Beijing, China

    Chang Feng, Yanan Xu & Yong Zhao

  4. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100101, China

    Yong Zhao

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Correspondence to Yong Zhao.

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Chu, Z., Feng, C., Sun, C. et al. Primed macrophages gain long-term specific memory to reject allogeneic tissues in mice. Cell Mol Immunol 18, 1079–1081 (2021). https://doi.org/10.1038/s41423-020-00521-7

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