The development of lymphoid organs can be viewed as a continuum. At one end are the 'canonical' secondary lymphoid organs, including lymph nodes and spleen; at the other end are 'ectopic' or tertiary lymphoid organs, which are cellular accumulations arising during chronic inflammation by the process of lymphoid neogenesis. Secondary lymphoid organs are genetically 'preprogrammed' and 'prepatterned' during ontogeny, whereas tertiary lymphoid organs arise under environmental influences and are not restricted to specific developmental 'windows' or anatomic locations. Between these two boundaries are other types of lymphoid tissues that are less developmentally but more environmentally regulated, such as Peyer's patches, nasal-associated lymphoid tissue, bronchial-associated lymphoid tissue and inducible bronchial-associated lymphoid tissue. Their regulation, functions and potential effects are discussed here.

Tertiary lymphoid tissues are lymph node-like cell aggregates that arise at sites of chronic inflammation. They have been observed in transplanted organs undergoing chronic rejection, but it is not known whether they contribute to the rejection process by supporting local activation of naïve lymphocytes. To answer this question, we established a murine transplantation model in which the donor skin contains tertiary lymphoid tissues due to transgenic expression of lymphotoxin-a (RIP-LT a ), whereas the recipient lacks all secondary lymphoid organs and does not mount primary alloimmune responses. We demonstrate in this model that RIP-LT a allografts that harbor tertiary lymphoid tissues are rejected, while wild-type allografts that lack tertiary lymphoid tissues are accepted. Wildtype allografts transplanted at the same time as RIP-LT a skin or 60 days later were also rejected, suggesting that tertiary lymphoid tissues, similar to secondary lymphoid organs, generate both effector and memory immune responses. Consistent with this observation, naive T cells transferred to RIP-LTa skin allograft but not syngeneic graft recipients proliferated and differentiated into effector and memory T cells. These findings provide direct evidence that tertiary lymphoid structures perpetuate the rejection process by supporting naïve T-cell activation.

Lymphotoxin-␣ (LT␣), IntroductionRecent years have seen great advances in the molecular understanding of lymphatic vessels and lymphangiogenesis. 1 Studies with genetically engineered mice identified several key growth factors, transcription factors, transmembrane glycoproteins, and signaling proteins that are crucial for lymphatic vessel development and function. [2][3][4][5] Varying deficiencies in these critical molecules resulted in a spectrum of lymphedema phenotypes ranging from edematous embryos with chylous ascites and severe vascular defects associated with perinatal lethality, 3,6 to more subtle manifestations of lymphatic function defects. [7][8][9] Derangements in the structure or function of lymphatic vessels may induce edema. 1 Chy mice, in which a heterozygous mutation in the Vegfr3 gene results in inactivation of vascular endothelial growth factor 3 (VEGFR-3) signaling, exhibit lymphedema only in the fore and hind paws despite an absence of lymphatics in the entire dermis, thus demonstrating the effectiveness of compensatory mechanisms. 9 Lymphangiogenesis has been shown to occur at the sites of inflammation in models of corneal transplantation and airway infection. [10][11][12] During chronic inflammation in autoimmunity, graft rejection and infection, chronic accumulations of lymphoid cells that resemble lymph nodes, termed "tertiary lymphoid organs" (TLOs) develop, many of which require members of the lymphotoxin (LT)/TNF family. 13 Lymphangiogenesis has been described in TLOs in thyroiditis, sialitis, rheumatoid arthritis, and chronic kidney graft rejection. [14][15][16][17] LTs, key mediators of inflammation through the induction of chemokines and vascular adhesion molecules, 18 also play crucial roles in lymphoid organ development. 19 The homotrimer LT␣ 3 is secreted by CD4 ϩ Th1, CD8 ϩ , NK, B, and lymphoid tissue inducer cells and signals through TNFR1 and TNFR2, explaining its partial redundancy to TNF␣ 3 , which signals through the same receptors. 20 TNF␣ is made by a wider variety of cells, including macrophages, in addition to the LT␣-producing lymphocytes. The LT␣ monomer also forms a heterotrimer with LT␤ that is required for the cell surface expression of the LT␣␤ complex. 21 The LT␣ 1 ␤ 2 complex binds to and signals through the LT␤R. Mice deficient in LT␣ lack all lymph nodes and Peyer patches, 19 whereas those deficient in LT␤ retain some cervical, sacral, and mesenteric lymph nodes. 22 Transgenic expression of mouse LT␣ under the control of the rat insulin promoter II (RIP) leads to its expression in the ␤ cells of the islets of Langerhans in the pancreas as expected, and in the skin 23 and proximal convoluted tubules of the kidney 23,24 as this promoter is somewhat "leaky." These mice develop accumulations of T and B cells, dendritic cells, follicular dendritic cells, and macrophages that are organized into TLOs that resemble lymph nodes in cellular composition and compartmentalization, the presence of high endothelial venules (HEVs) and lymphoid chemokine expression, 18,25 du...