CCR7: Unifying Disparate Journeys to the Lymph Node Free

Many immune responses begin in lymph nodes, and it is no wonder. The lymph node is the only tissue in the body that is primarily organized to be the perfect meeting point for cellular travelers that otherwise would seem to have a low probability to ever make an encounter. Through the high endothelial venule come lymphocytes that are otherwise confined to the blood, while from the lymph draining the parenchyma of an adjacent organ come Ag-bearing dendritic cells (DCs). Efficient interactions between these different cell types that originate from vastly different environments is made possible because the lymph node is specially designed, via its connections to both blood and lymphatic vasculatures, to bring them together. Whereas the journey that naive T lymphocytes take from the blood is very different from the journey that the DC takes through lymph, a single chemokine receptor, CCR7, governs both of these critical trafficking patterns, bringing molecular unity to two anatomically disparate journeys. The revelation that CCR7 governs both of these trafficking patterns was solidified in a single paper published in 1999 by Reinhold Förster, Martin Lipp, and their colleagues (1). Publication of this work followed on the heels of their report just a few years earlier that the chemokine receptor Burkitt’s lymphoma receptor 1 (BLR1; later called CXCR5) controlled B cell trafficking to lymphoid organs (2). Obviously, the team of Förster and Lipp were pivotal leaders in the quest to define the molecular pathways that govern the organization of lymphoid tissue.

With some nostalgia, let me bring the reader back to the 1990s, the decade in which chemokines were named and their biology unfolded, quite rapidly, for all to behold. The term chemokine, as a contraction of chemotactic cytokine, was selected in 1992 as international research mounted to recognize the existence of a structurally related, highly potent family of polypeptides that regulated immune cell chemotaxis (3). Prior to this time, known chemoattractants were lipid mediators such as leukotriene B₄ and platelet-activating factor, bacterial products like those containing formylated methionine at their N termini, or polypeptide fragments generated after activation of the complement cascade. All of these attractants were generated in the context of inflammation. As data on chemokine biology emerged, it became clear that some chemokines were homeostatic (4), produced constitutively, without a preceding inflammatory signal, and thus had the capacity to organize immune cells in preparation for an impending encounter with Ag or pathogen.

Förster and Lipp were part of the quest to relate chemokine pathways to the homeostatic organization of lymphoid tissue. The pace of progress in the field related to the unveiling of the central role of CCR7 in mediating both lymphocyte and DC homing to lymph nodes was astonishing. Throughout the 1990s, cloning strategies to identify new chemokines and new chemokine receptors yielded an onslaught of data. The laboratory of Martin Lipp in Berlin, Germany, cloned BLR1 in 1992 while comparing B cell lines to B cell–related tumors (5). Observing expression of its mRNA exclusively in lymphoid tissue, Lipp immediately proposed it might control homing of B cells (5) and went about proving this in a series of more than a half dozen papers prior to the pivotal demonstration of loss of B cell homing in the BLR1-deficient mouse his laboratory generated (2). Meanwhile, their work on BLR1 led to the identification of another related receptor in lymphocytes that they called BLR2 (6), which they quickly recognized was identical to a receptor (cloned by other groups) called EBV-induced 1 (EBI1) (7, 8). In contrast to the many papers on BLR1 that the laboratory published, Lipp published no follow-up studies on EBI1 until the Pillars of Immunology article (1) emerged in 1999, along with another related landmark study (9). This work revealed a critical role for CCR7 in controlling both T lymphocyte homing to lymph nodes across high endothelial venules and DC trafficking from skin. By then, the new name for EBI1 was CCR7 (10).

Other laboratories were, however, actively publishing data related to CCR7 in the intervening years. The laboratory of Osamu Yoshie in Osaka, Japan, cloned the two major chemotactic ligands for CCR7 in 1997 (10, 11), with recognition in 1998 that these ligands attracted T cells by binding to CCR7 (12, 13). These ligands are now called CCL19 and CCL21 using the new, more facile nomenclature that Zlotnik and Yoshie (14) devised. The speculations laid out by the Yoshie laboratory in 1998 made it clear they understood that CCR7 was likely to be a major regulator of T lymphocyte trafficking, as they predicted that trafficking of activated T lymphocytes in particular would rely on CCR7 (13), but they did not have the tools in hand to prove it. Meanwhile, Hideki Nakano, in another Japanese city in the same year, described a naturally occurring mutant mouse that exhibited a paucity of lymph node T cells (plt) due to a T cell trafficking defect (15). Although the specific mutations that accounted for their observations were not identified in 1998, it is clear from reading this paper that Nakano had his eye on chemokines and chemokine receptors. Could the anticipation of what was to come have been any more intense?

At the same time, four different laboratories were focusing on the expression of CCR7 in DCs. In the late 1990s, DC biology was exploding with the advent of tissue culture methodologies to dissect their cell biology. The laboratories of Christophe Caux, Federica Sallusto, Alberto Mantovani, and Yasunori Yamaguchi independently and simultaneously published the striking observation that CCR7 was upregulated on DCs that had matured to express optimal Ag presentation capacity, whereas they lost other chemokine receptors that were prominent in the immature stage of their life cycle (16–19). It was known that DC maturation was associated with homing to lymph nodes from tissues such as skin, a journey that involved DC entry into lymphatic vessels. Thus, the question emerged: does CCR7 direct this journey?

At least one of the DC groups listed above, the group of Federica Sallusto and Antonio Lanzavecchia, had an eye on CCR7 biology for both DCs and T cells. In collaboration with Förster and Lipp, in 1999, these investigators published the now popularized distinction between memory T cell pools, coining the terms central memory and effector memory T cells (9). It is amazing to reflect on the fact that the identification of these T cell pools was facilitated by tracking the expression of CCR7 and that the publication of this work, itself a Pillars of Immunology article recently reprinted in The Journal of Immunology, occurred in the same month as the description of phenotype in the CCR7 knockout (KO) mouse that linked CCR7 to naive T cell lymphocyte homing and DC trafficking to lymph nodes (1). Simultaneously, the plt/plt mouse was revealed by Nakano, Gunn, and colleagues (20) to have defects in expression of CCR7 ligands. In these papers, anticipation had transformed to a most exciting outcome: CCR7 and its ligands were linked to the recruitment of both T lymphocytes and DCs to lymph nodes. Thus, the chemokine–chemokine receptor pair that establishes the homeostatic lymph node environment crucial to immunity was identified.

Indeed, with all the anticipation that clearly had built up in the few years before Förster and Lipp published their findings on the CCR7 KO mouse, one might have expected several other groups to be hard at work generating their own CCR7 KO mouse. However, no other academic laboratories appeared to have been close enough to generating and characterizing a CCR7 KO mouse to allow other CCR7 KO strains to emerge in the literature at the same time or soon thereafter. Subsequent years of work, much coming from the Förster laboratory, would reveal striking details related to CCR7, including that it is CCR7 expressed by DCs in particular that conditions the lymph node to allow for appropriate T lymphocyte homing (21). In the lymphatic vasculature, the role of CCR7 in lymph trafficking is so prominent that it has been argued that nearly every cell that enters lymph, even the occasional neutrophil, must express CCR7 to do so.

Clearly, CCR7 has a rich past in immunology research. It also has a future. For instance, we still do not clearly understand the molecular events that conspire to turn on CCR7 transcription in activated DCs while dampening it in activated lymphocytes that become effector memory T cells. The excitement that centered on unraveling the role of CCR7 along with that of other chemokines/chemokine receptors in immunity and the rapid pace at which the discoveries were made and published in a wide array of journals are beautiful. In this commentary, it is an honor to celebrate this remarkable body of work.