LITERATURE Watch Implications for transplantation




While we have learned much about the immune system and devised many important and useful drugs, tolerance seems to remain a distant goal on the horizon. A new study shows that the tumor microenvironment may reveal some of the most important determinants of tolerance.

Anatomy of Tolerance

CITATION Shields JC, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 2010; 328: 749-752.


The cellular and molecular nature and mechanisms of tolerance continue to elude the field of transplantation. The certainties of the past that modulating signal one, signal two, signal three, T cells, B cells or antigen-presenting cells will generate tolerance have all yielded to the reality that while we have learned much about the immune system and devised many important and useful drugs, tolerance seems to remain a distant goal on the horizon. It is clear that modalities such as complete bone marrow chimerism will induce tolerance, but the expense and complications remain too high to contemplate wide dissemination of this approach at present. These failures and successes have demonstrated that tolerance is more complex than we initially understood, that it is an active process and not simply the elimination of a few clones, that it involves many different cell types and molecular pathways and that many fundamental discoveries likely remain. In fact, pregnancy and tumor progression show that tolerance is evident every day in clinical medicine, yet we do not fully understand such lessons at a level that allows us to apply them to transplantation.

In a revealing study, Shields et al. showed that the tumor microenvironment may be one of the most important determinants of tolerance. They observed that tumors that secreted high levels of the chemokine CCL21 were tolerated by the host immune system, continued to grow without inducing an immune response and could even protect other tumors that did not secrete CCL21 from the immune response, suggesting a state of infectious tolerance and active suppression. CCL21 and the closely related CCL19 are the ligands for the chemokine receptor CCR7. Together these receptor-ligand pairs form the major axis for organization of, and leukocyte recruitment to, the lymph nodes. Detailed investigation of the mechanisms in this tumor model showed that CCL21 recruited lymphoid tissue inducer cells (LTis) to the tumor. LTis are CCR7+CD45+CD3e–CD4+RORγt+ cells that express cell surface LTα1β2 and are essential in the organogenesis of lymph nodes. LTis in turn recruit a number of other cells to the tumors, including fibroblastic reticular cells (FRCs), which also express CCL19 and CCL21 along with the LTβR and gp38 (also called podoplanin), and are responsible for secreting the ER-TR7+ fibers that make up the stroma of the normal lymph node. In essence the CCL21-LTi-FRC axis creates what appears to be normal lymph node stroma. Subsequently recruited to this stroma are increased numbers of CD4+CD25+Foxp3+ regulatory suppressive T cells and CD11b+CD11c–F4/80–Gr1high myeloid-derived suppressor cells, along with increased expression of the immunosuppressive molecules TGF-β, indoleamine 2,3-dioxygenase and inducible nitric oxide synthase.

The implications of these findings for tumor immunology and for understanding tolerance in transplantation are that the stromal environment and the anatomy of the local immune response are critical features for determining positive versus negative outcomes in immunity. Many of the cells and molecular pathways that have been elucidated over the last two decades remain important in this paradigm, but now we are beginning to understand how to put the separate components together in three dimensions in the correct sequence over time. The observations of Shields et al. are in line with other reports in the literature showing that CCR7 deficiency can result in autoimmunity, that regulatory T cells are induced in lymph nodes and that disruption of normal secondary lymphoid structures can prevent transplantation tolerance. Nonetheless, important questions and counter examples remain. Thus, there were few B cells in the tumor lymphoid stroma of Shields et al., and others have shown that CCR7 deficiency can sometimes result in immunologic agnosia or tolerance. Critical questions that emerge from these studies are how to define the characteristics of tolerogenic versus immunogenic lymph nodes and stroma. What are the features of FRCs, LTis or stroma that determine the choice between immunity and suppression? Can we manipulate CCL19, CCL21, CCR7, LTαβ, LTβR or other molecules to take advantage of lymph node stromal regulatory properties? These considerations may lead to novel and unique experimental approaches to understanding tolerance, and to equally novel therapeutic implications for transplantation tolerance and the related problem of tumor immunity.