Dynamic Changes to Tissue-resident Immunity After MHC-matched and MHC-mismatched Solid Organ Transplantation
Prosser A, Huang WH, Liu L, et al. Cell Rep. 2021;35(7):109141.
It is well established that transplantation transfers tissue-resident cells (TRCs, also termed donor passenger leukocytes) together with the organ.1 In addition to these leukocytes that are known to migrate out of organs, tissue-resident lymphocytes have been described within organs, which do not recirculate in the peripheral blood or lymphatics.2 These cells are retained through specific migration and adhesion molecules and are crucial to the maintenance of antipathogen immunity as well as tissue integrity and repair.
In the study from Prosser et al,3 the authors compare the pool of tissue-resident lymphocytes before and after major histocompatibility complex (MHC)-matched and mismatched mouse liver and heart transplantation. The study identifies B cells, conventional and unconventional T cells, and innate lymphoid cells as TRCs. In MHC-matched liver transplantation, TRCs were retained while passenger leukocytes were detected in the peripheral lymphoid organs. However, in MHC-mismatched liver transplantation, virtually all TRCs were lost by day 28. Rapid recipient cell infiltration into the allograft was largely responsible for this loss of donor lymphocytes. The process did not take place in immunodeficient animals, highlighting the role of alloimmunity in TRC deletion. Importantly, recipient graft-infiltrating lymphocytes did not recreate the pretransplant donor organ lymphocyte composition, with significant phenotypic and functional differences observed even in MHC-matched transplants—albeit to a lesser degree. The overall phenotype of T cells showed an increase in expression of memory, exhaustion, and chemokine markers. Notably, the authors observed changes with similar dynamics in cardiac transplants, with even more donor lymphocytes lost (from a lower baseline level).
A key recent study has also shown that recipient effector T cells can differentiate into tissue-resident memory cells within the donor organ, where they contribute to transplant rejection.4 These cells can be identified by their specific transcriptional profile and are therefore potentially targetable. Further work is therefore needed to understand the impact of various immunosuppressive regimens on the composition of these donor- or recipient-derived TRCs.
Platelets Orchestrate the Resolution of Pulmonary Inflammation in Mice by T Reg Cell Repositioning and Macrophage Education
Rossaint J, Thomas K, Mersmann S, et al. J Exp Med. 2021;218(7):e20201353.
Although they are recognized for their role in hemostasis, platelets also demonstrate important immune functions. In recent years, it has become clear that platelets are vital for eliminating invading pathogens in acute respiratory distress syndrome (ARDS). ARDS is a common life-threatening disease and rare complication after solid organ transplantation typically accompanied by destructive hyperimmune responses.5 Timely resolution of such immune responses is key to restraining the attack of host tissue. The regulation of this process, however, is incompletely understood.
In their recent article in Journal of Experimental Medicine, Rossaint et al6 shed light on the role of platelets in the resolution of lung inflammation. Using a mouse model of bacteria-induced pneumonia, the authors demonstrate that depletion of platelets during the onset of inflammation prevents adequate neutrophil recruitment into the lung, leading to overwhelming and fatal bacterial dissemination. Conversely, depletion of platelets during the resolution phase led to significant lung damage. Intriguingly, this was found to result from the dichotomous behavior of platelets switching from preferentially binding neutrophils during the onset of inflammation, to binding regulatory T cells (Tregs) during the resolution phase. This was confirmed by the differential expression of surface adhesion molecules. During resolution, A disintegrin and metalloproteinase domain-containing protein 8-mediated expression of platelet-binding P-selectin glycoprotein ligand 1 (PSGL-1) on neutrophils decreased, whereas PSGL-1 expression on Treg increased. Meanwhile, expression of the PSGL-1 receptor P-selectin on platelets remained constant. Moreover, shedding of soluble CD40L by Tregs resulted in CD40-mediated platelet activation, provoking platelet–Treg aggregation and relocation to the lung. This physical interaction enabled platelets to elicit a transcriptomic shift in Tregs, instructing the release of the anti-inflammatory cytokines interleukin-10 and transforming growth factor-β. Strikingly, platelet–Treg aggregates also triggered macrophage transcriptomic polarization toward an anti-inflammatory and proresolution phenotype (of which distinct transcriptional programs have been previously defined7).
Altogether, Rossaint et al demonstrate the switch in cellular partnership of platelets from neutrophils during the early inflammatory response to Tregs and macrophages in the later resolution phase. The study elegantly demonstrates the mechanisms by which platelets partner with successive immune subsets to orchestrate both the initiation and resolution of inflammation, which may be important when considering the timing of antiplatelet therapies.
1. Prosser AC, Kallies A, Lucas M. Tissue-resident lymphocytes in solid organ transplantation: innocent passengers or the key to organ transplant survival? Transplantation. 2018;102:378–386.
2. Belz GT, Denman R, Seillet C, et al. Tissue-resident lymphocytes: weaponized sentinels at barrier surfaces. F1000Res. 2020;9:F1000 Faculty Rev–691.
3. Prosser A, Huang WH, Liu L, et al. Dynamic changes to tissue-resident immunity after MHC-matched and MHC-mismatched solid organ transplantation. Cell Rep. 2021;35:109141.
4. Abou-Daya KI, Tieu R, Zhao D, et al. Resident memory T cells form during persistent antigen exposure leading to allograft rejection. Sci Immunol. 2021;6:eabc8122.
5. Canet E, Osman D, Lambert J, et al. Acute respiratory failure in kidney transplant recipients: a multicenter study. Crit Care. 2011;15:R91.
6. Rossaint J, Thomas K, Mersmann S, et al. Platelets orchestrate the resolution of pulmonary inflammation in mice by T reg cell repositioning and macrophage education. J Exp Med. 2021;218:e20201353.
7. Chen HJ, Li Yim AYF, Griffith GR, et al. Meta-analysis of in vitro-differentiated macrophages identifies transcriptomic signatures that classify disease macrophages in vivo. Front Immunol. 2019;10:2887.