To the editor
In the June issue of Nature Medicine, Pratt et al.1 report on how local synthesis of the complement component C3 regulates acute renal transplant rejection. They present elegant experiments to show that renal allograft rejection is tempered in the absence of local production of C3. These findings, as described in the accompanying News & Views article2, underscore the often underappreciated role of the innate immune system in allograft rejection. However, the important question addressed in this study is how the complement system managed to markedly influence the immune process that leads to rejection. Unfortunately, the conclusions in this regard are vague.
The authors seem to imply in the Discussion section that local production of complement affects the priming of T cells by directly increasing the efficiency of T-cell engagement with donor antigen. However, it is not clear what T cells they are referring to. Are they naive T cells or previously primed T cells? Is it the engagement of naive T cells with antigen in the spleen or engagement of previously primed T cells with antigen in the graft? These are important distinctions as naive T cells and activated T cells have disparate homing patterns and activation requirements. Antigen-experienced (primed) T cells, such as effector and memory T cells, enter non-lymphoid tissues during inflammation and engage antigen there, whereas naive T-cell trafficking and antigen engagement seem to be restricted to secondary lymphoid organs3,4,5.
The data provided by the authors clearly demonstrate that previously primed T cells express complement receptors and that their proliferation to proximal tubular epithelial cells is defective in the absence of C3 production. However, no mention is made of whether naive T cells share these properties with their activated counterparts. Similarly, data are provided to show that activated T cells that express complement receptors can be found within graft tissue, but no data are provided to examine whether naive T cells enter the allograft. Therefore, we cannot eliminate the possibility that defective priming of naive T cells in the spleens of mice that received C3-deficient allografts is due to defective activation, migration and/or function of graft dendritic cells. The authors imply in their discussion that this possibility is low on their list because “...in vitro data suggest that locally produced C3 can exert an effect on T-cell function independently of B7 or MHC expression.” The authors, however, disregard the fact that what they studied in vitro were activated and not naive T cells. This confusion could have been avoided if precise terminology was used when referring to T cells: Are they naive or are they previously primed? Perhaps it is time for all of us who study transplantation immunology to exemplify the fundamental immunologists and mind our T-cell language.
References
Pratt, J.R., Basheer, S.A. & Sacks, S.H. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nature Med. 8, 582–587 (2002).
Kirk, A.D. Location, location, location: Regional immune mechanisms critically influence rejection. Nature Med. 8, 553–555 (2002).
Lakkis, F.G., Arakelov, A., Konieczny, B.T. & Inoue, Y. Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue. Nature Med. 6, 686–688 (2000).
Reinhardt, R.L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M.K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).
Chalasani, G., Dai, Z., Konieczny, B.T., Baddoura, F.K. & Lakkis, F.G. Recall and propagation of allospecific memory T cells independent of secondary lymphoid organs. Proc. Natl. Acad. Sci. USA 99, 6175–6180 (2002).
Kreisel, D. et al. Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: An alternative mechanism of allorecognition. Nature Med. 8, 233–239 (2002).
Briscoe, D.M. & Sayegh, M.H. A rendezvous before rejection: Where do T cells meet transplant antigens? Nature Med. 8, 220–222 (2002).
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Lakkis, F. Transplant rejection: Mind your T-cell language. Nat Med 8, 1043 (2002). https://doi.org/10.1038/nm1002-1043a
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DOI: https://doi.org/10.1038/nm1002-1043a
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