Lymph Drainage - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 183

also distal immunity via antigens introduced from nasal cavities. Nasal-associated
lymphoid tissue induces mucosal immune responses, such as the generation of T H1
and T H2 helper T cells, and IgA-committed B lymphocytes.
Addressins, extracellular ligands of lymphocyte-homing receptors in venular
endothelium, 13 are used to bind naive lymphocytes. High endothelial venules in
NALT contain peripheral node addressin (PNAd), either associated with mucosal
vascular addressin cell adhesion molecule MAdCAM1 or alone, whereas NALT
follicular dendritic cells express both MAdCAM1 and VCAM1 [ 326 ]. Naive
lymphocytes bind to NALT high endothelial venules predominantly via L-selectin
and PNAd rather than using

α 4 β 7 -integrin-MAdCAM1 interactions. Moreover,
MAdCAM1 and VCAM1 expressed by NALT follicular dendritic cells may recruit
and sequester lymphocytes [ 326 ].
Lymphoid tissue-inducer cells (LTi) that express TNFSF2-TNFSF3 heterotrimer
interact with local stromal organizer cells for NALT formation. 14 Consequently,
the production of adhesion molecules, such as vascular cellular adhesion molecule
VCAM1, intercellular adhesion molecule ICAM1, and mucosal addressin cell
adhesion molecule MAdCAM1, as well as the secretion of lymphocyte-homing
chemokines and cytokines rise. The TNFSF2-TNFSF3 2 complex engages its
cognate receptor TNFRSF3 on stromal cells and triggers the production of CCL19
and CCL21 as well as CXCL12 and CXCL13 chemokines [ 324 ]. The resultant
accumulation of B and T lymphocytes produces a second production wave of
TNFSF2-TNFSF3 2 heterotrimer that primes a positive feedback loop to further
enhance chemokine expression and cell recruitment. Chemokine CXCL13 primarily

13 Addressin is a member of the immunoglobulin superfamily. It interacts preferentially with
α 7 -integrin (a.k.a.

lymphocyte Peyer patch adhesion molecule LPAM) on leukocytes, and L-selectin to attract
immunocytes into mucosal and inflamed tissues.
14 CD3

β 1 -integrin (a.k.a. very late antigen VLA4 and CD49d) on myeloid cells, α β 4 4

LTi cells derive from fetal liver progenitors. They yield the earliest
cell type to colonize the lymphoid anlagen (cell aggregations in the embryo that serve as
first traces of a given type of structure; from German die Anlage [pl. Anlagen]: disposition,
arrangement (synonym: die Anordnung [formation], die Einrichtung); construction (synonym:
die Konstruktion); installation (synonym: die Installation), or primordium (initial clustering of
embryonic cells from which an organ develops; from Latin primus: first [chronologically] and
ordior: to begin, to initiate, to start), of secondary lymphoid organs. LTi-cell differentiation depends
on at least 2 transcription factors — inhibitor of DNA binding ID2, or bHLHb26, and ROR

− ,CD4 + ,PTPRc +

2,
or NR1f3-2 [ 327 ]. In the fetal liver, a subset of common lymphoid progenitors that expresses
the integrin-

γ

7 generates LTi cells under the control of the transcriptional repressor bHLHb26
and the nuclear receptor NR1f3-2 that are sequentially upregulated during 2 consecutive stages
of differentiation with opposite requirements for Notch signaling. Both bHLHb26 and Notch are
required for the generation of α 4 β 7 -integrin + , NR1f3-2 − fetal progenitors, thereby engaging the
LTi developmental axis, but Notch subsequently blocks the progression to the NR1f3-2 + stage
and final maturation of LTi cells, thus needing to be later repressed to avoid diversion to the
T-cell fate. Lymphoid tissue development is initiated during embryogenesis by the migration of
lymphoid tissue-inducer cells from the fetal liver to form lymph nodes and Peyer's patches. The
expression pattern changes during the transition from lymphoid tissue-inducer cells to lymphoid
tissue-organizer (LTo) cells in the lymph node anlagen, but not in the Peyer's patch primordia.

α β 4