Immunotherapy for Infectious Diseases

42 Boyaka and McGhee
Lymphocyte Homing in the GI Tract
Naive lymphocytes enter mucosal or systemic lymphoid tissues from the blood
through the endothelium via specialized high endothelial venules (HEVs) (43). In
GALT, HEV are present in the interfollicular zones rich in T-cells (44). The mucosal
addressin cell adhesion molecule-1 (MAdCAM-1) is the major addressin expressed by
Peyer’s patch HEV (45). The major homing receptors expressed by lymphocytes are
the integrins, which represent a large class of molecules characterized by a heterodimeric
structure of � and � chains. In general, expression of the �4 chain paired
with either �1 or �7 integrins differentiates between homing receptors for the skin or
gut, respectively. Thus, the �4�1 pair allows binding to vascular cell adhesion molecule-1
(VCAM-1) and is associated with homing to inflamed sites and skin (46,47).
Pairing of �4 with �7 represents the major integrin molecule responsible for lymphocyte
binding to MAdCAM-1 expressed on HEVs in Peyer’s patches (48). A number of studies
have now established that MAdCAM-1 is the major mucosal homing receptor ligand
(48-50). In addition to �4�7 integrin, L-selectin, which also binds to carbohydratedecorated
MAdCAM-1, is an important initial receptor for homing into GALT HEVs.
Interestingly, L-selectin is expressed on all naive lymphocytes; however, memory T- and
B-cells can be separated into �4�7 hi , L-selectin � , and L-selectin � subsets (51).
It is now clear that chemokines are directly involved in lymphocyte homing and that
they trigger arrest and cell activation via specific Gs�i receptors (52). For example, loss
of secondary lymphoid tissue chemokine (SLC) results in lack of naive T-cell or dendritic
cell migration into the spleen or Peyer’s patches (53). Furthermore, thymusexpressed
chemokine (TECK) mediated human memory T-cell migration into the
lamina propria of the GI tract. In fact, the gut homing �4�7 hi T-cells expressed a TECK
receptor, designated G-protein-coupled receptor-9-6, or CCR-9 (54). Interestingly,
human �E�7 � as well as �4�7 hi CD8 T-cells expressed CCR-9, suggesting that TECK-
CCR-9 is also involved in lymphocyte homing and arrest of intraepithelial lymphocytes
(IELs) into the GI tract epithelium (54).
Lymphocyte Homing in NALT and Lung-Associated Tissues
Unlike Peyer’s patch HEVs which are found in T-cell zones, murine NALT HEVs
are found in B-cell zones and express, peripheral node addressin ( PNAd) either alone
or associated with MAdCAM-1 (55). Furthermore, anti-L-selectin but not anti-
MAdCAM-1 Abs blocked the binding of naive lymphocytes to NALT HEV, suggesting
predominant roles for L-selectin and PNAd in the binding of naive lymphocytes to
these HEVs (55). In a rat model of antigen-induced lung inflammation, the percentage
of activated T-cells expressing �4 was increased in the bronchial lumen compared with
blood and lymph node T-cells after antigen challenge (56). An interesting approach
used to address the homing of human cells in the NALT was the analysis of tissuespecific
adhesion molecules after systemic, enteric, or nasal immunization (57). This
study showed expression of L-selectin by most effector B-cells induced by systemic
immunization, with only a small proportion expressing �4�7; the opposite was seen
after enteric (oral or rectal) immunization. Interestingly, effector B-cells induced by
intranasal immunization displayed a more promiscuous pattern of adhesion molecules,
with a large majority of these cells expressing both L-selectin and �4�7 (57).