Lymphocyte Homing and Homeostasis

VA Palo Alto Health Care System, Palo Alto, California, United States
Science (Impact Factor: 33.61). 05/1996; 272(5258):60-6. DOI: 10.1126/science.272.5258.60
Source: PubMed


The integration and control of systemic immune responses depends on the regulated trafficking of lymphocytes. This lymphocyte
“homing” process disperses the immunologic repertoire, directs lymphocyte subsets to the specialized microenvironments that
control their differentiation and regulate their survival, and targets immune effector cells to sites of antigenic or microbial
invasion. Recent advances reveal that the exquisite specificity of lymphocyte homing is determined by combinatorial “decision
processes” involving multistep sequential engagement of adhesion and signaling receptors. These homing-related interactions
are seamlessly integrated into the overall interaction of the lymphocyte with its environment and participate directly in
the control of lymphocyte function, life-span, and population dynamics. In this article a review of the molecular basis of
lymphocyte homing is presented, and mechanisms by which homing physiology regulates the homeostasis of immunologic resources
are proposed.

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    • "It is well known that parenteral vaccination is not very effective in inducing protection against intestinal infections [19]. Recent studies have shown that the main reason for this phenomenon is that B-and T-cell priming in the lymphoid organs of the intestinal mucosa induces the homing receptor constituted by the integrin ␣4␤7 and the chemokine receptor CCR9 [20] [21]. However, these receptors are not induced peripherally, since the DCs present in the intestinal lymphoid organs (and other mucosa, like the upper respiratory track) secrete retinoic acid at the moment of the B-and T-cell priming [22] [23]. "
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    ABSTRACT: Rotavirus (RV) is the primary etiologic agent of severe gastroenteritis in human infants. Although two attenuated RV-based vaccines have been licensed to be applied worldwide, they are not so effective in low-income countries, and the induced protection mechanisms have not been clearly established. Thus, it is important to develop new generation vaccines that induce long lasting heterotypic immunity. VP6 constitutes the middle layer protein of the RV virion. It is the most conserved protein and it is the target of protective T-cells; therefore, it is a potential candidate antigen for a new generation vaccine against the RV infection. We determined whether targeting the DEC-205 present in dendritic cells (DCs) with RV VP6 could induce protection at the intestinal level. VP6 was cross-linked to a monoclonal antibody (mAb) against murine DEC-205 (αDEC-205:VP6), and BALB/c mice were inoculated subcutaneously (s.c.) twice with the conjugated containing 1.5μg of VP6 in the presence of polyinosinic-polycytidylic acid (Poly I:C) as adjuvant. As controls and following the same protocol, mice were immunized with ovalbumin (OVA) cross-linked to the mAb anti-DEC-205 (αDEC-205:OVA), VP6 cross-linked to a control isotype mAb (Isotype:VP6), 3μg of VP6 alone, Poly I:C or PBS. Two weeks after the last inoculation, mice were orally challenged with a murine RV. Mice immunized with α-DEC-205:VP6 and VP6 alone presented similar levels of serum Abs to VP6 previous to the virus challenge. However, after the virus challenge, only α-DEC-205:VP6 induced up to a 45% IgA-independent protection. Memory T-helper (Th) cells from the spleen and the mesenteric lymph node (MLN) showed a Th1-type response upon antigen stimulation in vitro. These results show that when VP6 is administered parenterally targeting DEC-205, it can induce protection at the intestinal level at a very low dose, and this protection may be Th1-type cell dependent. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 04/2015; 33(35). DOI:10.1016/j.vaccine.2015.03.080 · 3.62 Impact Factor
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    • "To mount an effective immune response, T and B lymphocytes must migrate into tissue, which depends on the regulated trafficking of lymphocytes [10]. This 'homing' process eventually leads to the recruitment of immune effector cells to sites of antigenic or microbial invasion. "
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    ABSTRACT: A variety of ion channels has been discovered in lymphocytes. RT-PCR and real-time PCR analysis revealed that ALL (acute lymphocytic leukemia) cell lines and human peripheral blood mononuclear cells mainly expressed TTX (tetrodotoxin)-sensitive voltage-gated sodium channels (VGSCs). Expression of VGSC protein was confirmed by western blots and Immunofluorescence. Whole-cell patch-clamp recordings showed that a sub-population (20%) of MOLT-4 cells expressed functional VGSCs, which were TTX-sensitive. Importantly, 2 μM TTX decreased the invasion of Jurkat and MOLT-4 cells ∼90%. These results indicate that the activity of VGSCs could represent a novel mechanism potentiating the invasive capacity of these cells.
    Biochemical and Biophysical Research Communications 01/2015; 247(2). DOI:10.1016/j.bbrc.2015.01.103 · 2.30 Impact Factor
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    • "Delineating the specific nuclear receptors governing these events is needed for the refinement of retinoid-based therapies. Since cell adhesion and migration are paramount in immunity, the particular role of retinoids in these processes has been an area of particular interest [19] [20]. Seminal studies have established that atRA bestows gut homing properties to lymphocytes [21] [22] [23]. "
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    ABSTRACT: Oxidative metabolites of vitamin A, in particular all-trans-retinoic acid (atRA), have emerged as key factors in immunity by specifying the localization of immune cells to the gut. Although it is appreciated that isomers of retinoic acid activate the retinoic acid receptor (RAR) and retinoid X receptor (RXR) family of nuclear receptors to elicit cellular changes, the molecular details of retinoic acid action remain poorly defined in immune processes. Here we employ a battery of agonists and antagonists to delineate the specific nuclear receptors utilized by retinoids to evoke lymphocyte cell adhesion to ADAM (a disintegrin and metalloprotease) protein family members. We report that RAR agonism is sufficient to promote immune cell adhesion in both immortal and primary immune cells. Interestingly, adhesion occurs independent of integrin function, and mutant studies demonstrate that atRA-induced adhesion to ADAM members required a distinct binding interface(s) as compared to integrin recognition. Anti-inflammatory corticosteroids as well as 1,25-(OH)(2)D-3, a vitamin D metabolite that prompts immune cell trafficking to the skin, potently inhibited the observed adhesion. Finally, our data establish that induced adhesion was specifically attributable to the RAR-alpha receptor isotype. The current study provides novel molecular resolution as to which nuclear receptors transduce retinoid exposure into immune cell adhesion.
    Biochemical and Biophysical Research Communications 10/2014; 454(4). DOI:10.1016/j.bbrc.2014.10.120 · 2.30 Impact Factor
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